Dosing Regimens Associated With Extended Release Paliperidone Injectable Formulations

ABSTRACT

The present invention provides methods of treating patients with long acting injectable paliperidone palmitate formulations. The disclosure includes methods for mitigating at least one adverse change in blood lipid levels of a patient in need thereof who has been treated with a paliperidone palmitate extended-release injectable suspension at either one-month intervals (PP1M) or three-month intervals (PP3M), comprising transitioning the patient to a paliperidone palmitate extended-release injectable suspension having a six month dosing interval (PP6M).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 63/235,331, filed Aug. 20, 2021, the disclosure of whichis incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to methods of treating a psychiatric patient inneed of treatment with long acting injectable paliperidone palmitateformulations, including methods for mitigating adverse changes in thepatient's blood lipid profile.

BACKGROUND OF THE INVENTION

Antipsychotic medications are the mainstay in the treatment ofschizophrenia, schizoaffective disorder, and schizophreniform disorders.Antipsychotics were first introduced in the mid-1950s. These typical orfirst generational drugs are usually effective in controlling thepositive symptoms of schizophrenia but are less effective in moderatingthe negative symptoms or the cognitive impairment associated with thedisease. Atypical antipsychotics or second generation drugs, typified byrisperidone and olanzapine, were developed in the 1990s, and aregenerally characterized by effectiveness against both the positive andnegative symptoms associated with schizophrenia.

Paliperidone palmitate is the palmitate ester of paliperidone(9-hydroxy-risperidone), a monoaminergic antagonist that exhibits thecharacteristic dopamine D2 and serotonin (5-hydroxytryptamine type 2A)antagonism of the second generation, atypical antipsychotic drugs.Paliperidone (9-OH risperidone) is the major active metabolite ofrisperidone. Extended release (ER) osmotic controlled release oraldelivery (OROS) paliperidone, as a tablet formulation, is marketed inthe United States (U.S.) for the treatment of schizophrenia andmaintenance of effect.

Paliperidone palmitate has been developed as a long-acting,intramuscular (i.m.), injectable aqueous nanosuspension for thetreatment of schizophrenia and other related diseases that are normallytreated with antipsychotic medications. Because of extreme low watersolubility, paliperidone esters such as paliperidone palmitate dissolveslowly after an intramuscular injection before being hydrolyzed topaliperidone and made available in the systemic circulation.

Many patients with mental illnesses achieve symptom stability withavailable oral antipsychotic medications; however, it is estimated thatup to 75% have difficulty adhering to a daily oral treatment regimen,i.e. adherence problems. Problems with adherence often result inworsening of symptoms, suboptimal treatment response, frequent relapsesand re-hospitalizations, and an inability to benefit from rehabilitativeand psychosocial therapies. Once monthly Paliperidone palmitateinjection has been developed to provide sustained plasma concentrationsof paliperidone, which may greatly enhance compliance with dosing.Paliperidone palmitate formulated as an aqueous nanosuspension isdescribed in U.S. Pat. Nos. 6,077,843 and 6,555,544, each of which isincorporated herein by reference. In addition, dosing regimens ofpaliperidone palmitate for treating patients is disclosed in U.S. Pat.Nos. 9,439,906 and 10,143,693, each of which is incorporated herein byreference.

Paliperidone palmitate is an atypical antipsychotic drug administered byintramuscular injection. The original formulation of paliperidonepalmitate was a once-monthly antipsychotic and was approved for thetreatment of schizophrenia in adults in numerous countries. The acuteand sustained efficacy and tolerability profile of once-monthlypaliperidone palmitate has been demonstrated in clinical studiestotaling more than 3800 patients. Continued treatment with once-monthlypaliperidone palmitate in patients who initially responded to it foracute worsening of symptoms resulted in a nearly 4-fold reduction inrelapse risk compared with patients randomized to placebo. A laterdeveloped three-month formulation offers a substantially longer dosinginterval: injections are administered once every three months. Thisextended dosing interval offers the prospect of fewer opportunities fornonadherence than previously available long acting injectableformulations, thus reducing relapse risk as a result of subtherapeuticplasma concentration and its associated negative consequences inpatients with schizophrenia.

Paliperidone is currently available for therapeutic use in 3formulations: an oral extended-release formulation (INVEGA® ExtendedRelease [ER] tablets; also termed INVEGA® prolonged-release [PR]tablets), and two long-acting injectable (LAI) formulations(paliperidone palmitate one-month injection [INVEGA SUSTENNA® orXEPLION®] and paliperidone palmitate three-month injection [INVEGATRINZA® or TREVICTA®]). As disclosed herein, another paliperidonepalmitate product intended for administration once every six months(paliperidone palmitate six-month injection), with a view to furtherimproving adherence and convenience, is being developed.

Patients who do not regularly take their medications can suffer manyconsequences, most notably schizophrenia relapse. For oralantipsychotics, medication gaps of as little as one day can double therisk for re-hospitalization. This typically results in worsening ofpsychiatric comorbidities, loss of employment, interruption of educationand impairment of family relationships. The biological consequencesinclude loss of synaptic plasticity of neurons, especially in thefrontal lobes. Functionally schizophrenia relapse has been linked topruning at the level of synaptic neuronal junctions. Overall, this canbe radiologically measured by widespread shrinkage of the grey matter ofthe brain, with accompanying enlargement of the cerebral ventricles.These changes are visible on CT/MRI scanning of the brain. With eachsuccessive relapse, further progressive changes to the brain aretypically observed. Currently there is no known cure for schizophrenia,and the only proven method to treat the disease is with long-termadministration of antipsychotic medications along with social andbehavioral interventions. The strongest predictor of schizophreniarelapse is adherence to antipsychotic medications.

A paliperidone palmitate product that is intended to be given once everysix months presents a challenge in terms of a patient remembering tocome in for treatment at exactly the six-month time point. This isfurther compounded by the fact that the length of a month varies between28-31 days. Because an injection is intended to be given by a healthcare professional, and not self-administered, allowing patients to haveflexibility to schedule their visit to the clinic and receive theirinjection is an important consideration. Most other antipsychoticregimens (oral and LAI) are typically given over a one-month cycle, andpatients return to a clinic to either get a refill of their prescriptionor an injection. A six-month dosing interval presents a unique challengeto ensure compliance.

Patients also at times miss their doses of medication. Consequently,there is a need to re-initiate a dosing regimen for patients who misstheir regularly scheduled dose of medication.

Moreover, metabolic side effects (including blood lipid shifts) are acommon challenge in the treatment of patients requiring antipsychoticmedication. During long-term treatment with antipsychotic drugs inpatients with schizophrenia or schizoaffective or any other psychoticdisorder, these cardiovascular risk factors increase and can negativelyimpact patients' long-term morbidity and even mortality. But not onlythe medical perspective is an important one. Patients with severe mentaldisorders face long-term pharmacological treatment and long-termmetabolic side-effects, and face not only the risk of drug-druginteractions but also a reduction of quality of life and potentiallyeven stigmatization. Especially for young patients in early stages oftheir illness and with many years of treatment ahead of them, apreventive approach to improve long-term medical outcomes is critical tohelp maintain their social life, reduce stigma, and increase quality oflife. Any potential for avoiding worsening in blood lipid levels wouldbe a benefit for patients treated with risperidone or paliperidone whoare in need of long-term symptom protection.

SUMMARY OF THE INVENTION

The present disclosure provides methods for mitigating adverse changesin the blood lipid profile of a patient in need thereof who has beentreated with a paliperidone palmitate extended-release injectablesuspension at either one-month intervals (PP1M) or three-month intervals(PP3M), comprising transitioning the patient to a paliperidone palmitateextended-release injectable suspension having a six month dosinginterval (PP6M). The transition is typically accomplished byadministering to the patient a last dose of the PP1M or the PP3M andthen administering an initial dose of the PP6M.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a flow chart of a double-blind, randomized,active-controlled, parallel-group study of paliperidone palmitatesix-month formulation.

FIG. 2 depicts a Kaplan-Meier plot of time to relapse during thedouble-blind phase up to month 12.

FIG. 3 depicts a Forest plot of estimated percentage (95% CI) ofsubjects that remained relapse free at month 12.

FIG. 4 depicts median plasma concentration time profiles of paliperidoneafter administration of PP3M (350 mg eq. or 525 mg eq.) and PP6M (700 mgeq. or 1000 mg eq.) in a double-blind study.

FIG. 5 depicts a comparison of PK plasma concentration and clinicalefficacy (median time to relapse) across paliperidone formulations.

FIG. 6 depicts missed dose simulations for when >6 months and 3 weeksand up to 8 months have elapsed since the last steady-state 1000 mg eq.PP6M injection (7 months, and 7.5 months after the last PP6M dose).

FIG. 7 depicts missed dose simulations when between 8 months up to andincluding 11 months have elapsed since the last 1000 mg eq. PP6Minjection (8, 10 and 11 months after the last PP6M dose).

FIG. 8 depicts missed dose simulations for when >11 months have elapsedsince the last 1000 mg eq. PP6M injection (12, 15 and 18 months afterthe last PP6M dose).

DETAILED DESCRIPTION

The presently disclosed inventive subject matter may be understood morereadily by reference to the following detailed description taken inconnection with the accompanying examples, which form a part of thisdisclosure. It is to be understood that these inventions are not limitedto the specific formulations, methods, or parameters described and/orshown herein, and that the terminology used herein is for the purpose ofdescribing particular embodiments by way of example only and is notintended to be limiting of the claimed inventions.

When a value is expressed as an approximation by use of the descriptor“about” or “substantially” it will be understood that the particularvalue forms another embodiment. In general, use of the term “about” or“substantially” indicates approximations that can vary depending on thedesired properties sought to be obtained by the disclosed subject matterand is to be interpreted in the specific context in which it is used,based on its function.

It is to be appreciated that certain features of the invention whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.That is, unless obviously incompatible or excluded, each individualembodiment is deemed to be combinable with any other embodiments andsuch a combination is considered to be another embodiment. Conversely,various features of the invention that are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any sub-combination.

Where present, all ranges are inclusive and combinable. For example,when a range of “1 to 5” is recited, the recited range should beconstrued as optionally including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2& 4-5”, “1-3 & 5”, and the like. In addition, when a list ofalternatives is positively provided, such a listing can also includeembodiments where any of the alternatives may be excluded. For example,when a range of “1 to 5” is described, such a description can supportsituations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, arecitation of “1 to 5” may support “1 and 3-5, but not 2”, or simply“wherein 2 is not included.”

As used herein, “PP1M” refers to a paliperidone palmitateextended-release injectable suspension or other type of formulationhaving an amount of paliperidone palmitate suitable for a dosinginterval of about one-month. For example, PP1M can refer to apaliperidone palmitate extended-release injectable suspension having anamount of paliperidone palmitate suitable for a dosing interval of aboutone-month. A commercially available example includes INVEGA SUSTENNA® orXEPLION®. See also U.S. Pat. No. 9,439,906 incorporated herein byreference. In one embodiment, PP1M is administered by intramuscularinjection. In one embodiment, PP1M is administered by intramuscularinjection into a deltoid muscle or a gluteal muscle. In one embodiment,PP1M is administered by intramuscular injection into a deltoid muscle.In one embodiment, PP1M is administered by intramuscular injection intoa gluteal muscle.

As used herein, “PP3M” refers to a paliperidone palmitateextended-release injectable suspension or other type of formulationhaving an amount of paliperidone palmitate suitable for a dosinginterval of about three-months. For example, PP3M can refer to apaliperidone palmitate extended-release injectable suspension having anamount of paliperidone palmitate suitable for a dosing interval of aboutthree-months. A commercially available example includes INVEGA TRINZA®or TREVICTA®. See also U.S. Pat. No. 10,143,693 incorporated herein byreference. In one embodiment, PP3M is administered by intramuscularinjection. In one embodiment, PP3M is administered by intramuscularinjection into a deltoid muscle or a gluteal muscle. In one embodiment,PP3M is administered by intramuscular injection into a deltoid muscle.In one embodiment, PP3M is administered by intramuscular injection intoa gluteal muscle.

As used herein, “PP6M” refers to a paliperidone palmitateextended-release injectable suspension or other type of formulationhaving an amount of paliperidone palmitate suitable for a dosinginterval of about six-months. For example, PP6M can refer to apaliperidone palmitate extended-release injectable suspension having anamount of paliperidone palmitate suitable for a dosing interval of aboutsix-months. A commercially available example includes INVEGA HAFYERA™ orBYANNLI®.

Paliperidone is effective for the treatment of psychosis and has beenused to treat schizophrenia and schizoaffective disorders. Accordingly,PP6M is suitable for the treatment of psychotic disorders including butnot limited to schizophrenia and/or schizoaffective disorder or bipolardisorder.

PP6M is typically administered to patients who have been adequatelytreated with PP1M (e.g. INVEGA SUSTENNA®) for several months, and, incertain embodiments, for at least four months, with PP1M doses of about156 mg or about 234 mg paliperidone palmitate. It is further preferredthat the last two doses of PP1M are at the same dosage strength beforestarting PP6M. Alternatively, PP6M is administered to patients who havebeen adequately treated with PP3M (e.g. INVEGA TRINZA®) for at least onethree-month cycle, with PP3M doses of about 546 mg or about 819 mgpaliperidone palmitate.

PP6M will typically be provided with a dose in the range of from about1000 mg to about 1600 mg of paliperidone palmitate to provide asustained therapeutic concentration of paliperidone over the six-monthdosing interval. Preferably, the PP6M is provided in dose strengths ofabout 1092 mg or about 1560 mg paliperidone palmitate. The drug producthydrolyzes to the active moiety, paliperidone, resulting in dosestrengths of about 700 mg eq. or 1000 mg eq. of paliperidone,respectively.

PP6M is preferably provided in a prefilled syringe(cyclic-olefin-copolymer) prefilled with either 700 mg eq. (3.5 mL) or1000 mg eq. (5.0 mL) paliperidone (as 1092 mg or 1560 mg paliperidonepalmitate, respectively) with a plunger stopper, a plunger rod, and tipcap (bromobutyl rubber), a backstop, and a needle, preferably a thinwalled 20 gauge (G), 1½-inch safety needle.

PP6M is intended for intramuscular use. It is not recommended toadminister by any other route. Care should be taken to avoid inadvertentinjection into a blood vessel. Doses are preferably administered in asingle injection; for example, divided injections could change therelease profile. It is otherwise preferred that injections beadministered slowly, deep into the muscle of the patient, in particular,a deltoid or gluteal muscle. Typically, PP6M is administered to agluteal muscle given the volume of the injection. In one embodiment,PP6M is administered by intramuscular injection. In one embodiment, PP6Mis administered by intramuscular injection into a gluteal muscle.

It should be understood that references herein to methods of treatment(e.g. methods for mitigating adverse changes in the blood lipid profileof a patient in need thereof) using one or more compounds orformulations thereof (e.g. a paliperidone palmitate extended-releaseinjectable suspension) should also be interpreted as references to:

one or more compounds or formulations thereof (e.g. a paliperidonepalmitate extended-release injectable suspension) for use in methods oftreatment (e.g., methods for mitigating adverse changes in the bloodlipid profile of a patient in need thereof); and/or

the use of one or more compounds or formulations thereof (e.g. apaliperidone palmitate extended-release injectable suspension) in themanufacture of a medicament for treating a pathological condition (e.g.,adverse changes in the blood lipid profile of a patient in needthereof).

Intramuscular Injection

Typically, regardless of the patient's weight, PP6M is administeredintramuscularly using a thin walled syringe, for example, a 20 gauge(G), 1½-inch needle in a deltoid muscle or a gluteal muscle. To theextent administered to a deltoid muscle, paliperidone palmitate istypically administered into the center of a deltoid muscle, preferablyalternating between the two deltoid muscles per single injection (i.e.the opposite deltoid muscle is used at the next scheduled dosinginterval). For PP6M, gluteal intramuscular administration is preferred.For example, PP6M may be administered into the upper-outer quadrant of agluteal muscle. It is also preferred that gluteal injections should bealternated between the two gluteal muscles per single injection (i.e.the opposite gluteal muscle is used at the next scheduled dosinginterval).

Incomplete Administration

PP6M is typically a highly concentrated product. As a result, animportant consideration is to ensure complete suspension/resuspension ofthe product before administration. To avoid an incompleteadministration, the syringe is shaken and/or mechanically agitated toobtain a uniform dispersion of the suspension. For example, the syringeis preferably shaken fast with the syringe tip cap pointing up for atleast 15 seconds. A brief rest may be taken, and then the syringe maybe, and preferably is, shaken again for another 15 seconds. Theinjection is then preferably done immediately or within 5 minutes of thelast shaking to ensure resuspension and that the needle does not getclogged during injection.

Due to the slow release characteristics of PP6M, the product is notintended to be used in patients who are immediately transitioning fromoral to LAI antipsychotic therapy. Rather, PP6M is intended to be usedin patients who are adequately treated with either PP1M or PP3M at thetime of initiation of PP6M. The determination of adequately treated istypically up to the judgment of the prescribing clinician. Typically,PP6M dosing is initiated: A) one month after being adequately treatedwith PP1M (e.g. INVEGA SUSTENNA®) for at least four months; or B) threemonths after a PP3M (e.g. INVEGA TRINZA®) dose has been established asadequate treatment. PP6M may be administered one month (±7 days) after alast PP1M injection, or three months (±14 days) after a last PP3Minjection.

Following the initial PP6M injection, PP6M should be administered everysix months. If needed, dose adjustment can be made every six months inincrements within the range of 1092 mg to 1560 mg paliperidone palmitatebased on individual patient tolerability and/or efficacy. Typically, thedosage is adjusted to about 1092 mg or to about 1560 mg paliperidonepalmitate. Due to the long-acting nature of PP6M, the patient's responseto an adjusted dose may not be apparent for several months.

Dosing Window

As noted herein, nonadherence is a major issue in the treatment ofpsychiatric patients, especially those with schizophrenia, who oftenabruptly discontinue medication without consulting their practitioner orcaregiver. Lack of adherence has been identified as the strongestpredictor of relapse, which typically results in worsening ofpsychiatric comorbidities, loss of employment, interruption of educationand impairment of family relationships. For oral antipsychotics,medication gaps of as little as one day can double the risk forre-hospitalization. Long acting injectable (LAI) antipsychotics weredeveloped to address this problem and to ensure timely interventions fornon-adherent patients to prevent relapse and hospitalization.

The commonly encountered difficulty in clinical practice, however, isthat subjects need to return to the clinic on a specific date afterreceiving their previous maintenance injection of a LAI antipsychotic.Having a window in which injections could be given would give greaterflexibility to prescribers, patients, and caregivers. This window willoften be prescribed by a medical professional and/or set by a regulatoryagency.

Previously, a dosing window of ±1 week around the target injection date(scheduled injection date based on dosing interval) was established forPP1M. For PP3M, this window was expanded to ±2 weeks around the targetinjection date. It has now been found that a dosing window of up to 2weeks earlier and up to 3 weeks after the target injection date for PP6Mmay be used, offering further dosing flexibility.

Dosing recommendations have historically been aimed at paliperidoneplasma concentrations above a threshold of 7.5 ng/mL. This threshold hasbeen associated with a central Dopamine type 2 (D2) receptor occupancyof 60% while receptor occupancy in the range of 60%-80% is considerednecessary for a satisfactory antipsychotic response. As reflected in theexample section (see Example 7), simulations were conducted to evaluatethe relationship between median time to relapse and the point at whichthe median paliperidone concentration goes under 7.5 ng/mL. An apparentdelay lasting from several weeks to several months was observed betweenthe time point when median plasma paliperidone concentration decreasedto 7.5 ng/mL and the median time to relapse, i.e., the time point whenhalf of the subjects had experienced relapse, while the other half ofthe subjects either relapsed later or did not relapse during the study.Thus, it appears that the therapeutic effect is more prolonged than theexpected effect based on the 7.5 ng/mL threshold, and the relapseprotection window may be extended farther in the positive direction.

In one embodiment, a dosing window of up to 2 weeks earlier and up to 3weeks after the target injection date for PP6M (i.e. the scheduledsix-month time point) is used. Accordingly, the disclosure includesmethods for administering paliperidone palmitate to a patient in needthereof who has been administered a first dose of a paliperidonepalmitate extended-release injectable suspension, comprisingadministering a second dose of the paliperidone palmitateextended-release injectable suspension to a deltoid or gluteal muscle,preferably a gluteal muscle, of the patient up to two weeks before orthree weeks after a time that is six months after administration of thefirst dose, without an intervening dose of paliperidone palmitatebetween the first dose and the second dose. It should be recognized thatthe first dose and the second dose are doses within the sequence of thedescribed methods, but do not necessarily refer to the very first(initial) or second dose administered to the patient.

Unless otherwise indicated, as used herein, a “month” refers to aGregorian calendar month and may vary from as little as 28 days (e.g.,February) to 31 days (e.g., October), e.g., 28, 29, 30, or 31 days. Thesix-month time point reflects six consecutive calendar months. Asindicated herein, certain testing reflected in the examples, includingsimulations, were based on 30 days being used for a month. A “week”refers to seven days.

In some embodiments, other dosing windows may be considered. Forexample, a dosing window of up to one week earlier and up to two weeksafter, or up to one week earlier and up to three weeks after, or up totwo weeks earlier and up to two weeks after, the target injection datefor PP6M. In still other embodiments, the second dose is administered upto four weeks, or up to five weeks after a time that is six months afteradministration of the first dose as part of a dosing window. Anycombination of these time periods before and after a time that is sixmonths after administration of the first dose may be utilized. Incertain embodiments, the dosing window is applied to patients that havereached a steady-state paliperidone plasma concentration.

The first dose and second dose, independently, are typically from about1000 mg to about 1600 mg of paliperidone palmitate. In particular, thefirst dose and second dose, independently, are about 1092 mg or about1560 mg paliperidone palmitate. In other embodiments, the first dose andthe second dose are each about 1092 mg paliperidone palmitate. Inanother embodiment, the first dose and second dose are each about 1560mg paliperidone palmitate.

Typically, the plasma concentration of paliperidone in the patient isabout 5 to about 50 ng/mL at the time of the second dose, or about 10 toabout 40 ng/mL at the time of the second dose. For example, when thefirst dose is 1092 mg paliperidone palmitate, the plasma concentrationof paliperidone in the patient is about 5 to about 30 ng/mL, or about 10to about 25 ng/mL, at the time of the second dose. When the first doseis 1560 mg paliperidone palmitate, the plasma concentration ofpaliperidone in the patient is about 9 to about 40 ng/mL, or about 20 toabout 30 ng/mL, at the time of the second dose. In this context, “at thetime of the second dose” refers to concentration levels immediatelypreceding the second dose, typically representing C_(trough) values.

In other aspects, the plasma concentration of paliperidone in thepatient achieves a peak of about 10 to about 150 ng/mL afteradministration of the second dose, or about 35 ng/mL to about 125 ng/mLafter administration of the second dose. For example, when the firstdose is 1092 mg paliperidone palmitate, the plasma concentration ofpaliperidone in the patient achieves a peak of about 10 to about 125ng/mL, or about 50 to about 90 ng/mL, after administration of the seconddose. When the first dose is 1560 mg paliperidone palmitate, the plasmaconcentration of paliperidone in the patient achieves a peak of about 35to about 145 ng/mL, or about 70 to about 110 ng/mL, after administrationof the second dose.

In certain embodiments, PP3M and PP6M can have the same formulation. Insuch an embodiment, the pharmacokinetic properties of PP6M will besimilar to PP3M, but such a PP6M would be expected to have higher peaksand lower troughs given the higher amount of drug and longer frequencyof administration. As shown in Example 6, the absolute drug plasmaconcentrations were lower for PP6M at its target interval vs. PP3M atits target interval. Given that PP3M had established a dosing window of±2 weeks around the target injection date, expanding the dosing windowin the positive direction for a formulation that results in lower drugplasma concentrations at the target interval point would not have beensuggested. But, as reflected herein, it was discovered that thetherapeutic effect is more prolonged than the expected effect based onpharmacokinetic data, thus allowing the dosing window to extend fartherin the positive direction.

Missed Doses

Patients who receive LAI antipsychotics routinely return to their healthcare provider to receive injections of their medication. The timing oftheir dose is typically carefully prescribed. As noted herein, for anygiven antipsychotic an optimal dosing cycle is recommended, along with adosing window (±) in which they can receive their medication without anyuntoward side effects or loss of efficacy. In the present disclosure,following an initial dose of PP6M, PP6M should be administered every sixmonths. Missed doses of PP6M should be avoided, although injectionsgiven within the prescribed dosing window would not be considered amissed dose. If needed, dose adjustment can be made every six monthsbetween the dose levels of 1092 mg to 1560 mg paliperidone palmitatebased on individual patient tolerability and/or efficacy.

However, despite this, it is a frequent occurrence for schizophreniapatients to become noncompliant at some point during their illness.Therefore, based on population pharmacokinetic simulations, guidelinesare provided in the event of missed doses of PP6M beyond thedosing-window.

The present disclosure provides a mechanism by which patients can resumetreatment with PP6M in case they become fully or partially non-adherent.Since dosing of PP6M is dependent on a patient first being stabilized onPP1M/PP3M, this would reduce the necessity of patients having to startde-novo. In addition, because it was discovered that the therapeuticeffect is more prolonged than the expected effect based onpharmacokinetic data, patients that had at least one PP6M injection areexpected to be relapse-free for a longer period of time. This provides apositive effect of PP6M on preventing relapse, even in situations ofnon-adherence.

The disclosure provides re-initiation dosing regimens for patients whomiss their regularly scheduled dose of medication, i.e., are outside theprescribed dosing window, with the regimen depending on the time elapsedfrom the patient's last dose. In some embodiments, the missed dose isover six months and three weeks, but less than seven to nine months,e.g. less than eight months, after the last injection.

For example, to the extent the dosing window is up to 2 weeks earlierand up to 3 weeks after the target injection date, the disclosureprovides a method for administering paliperidone palmitate to a patientin need thereof who has been administered a first dose of a firstpaliperidone palmitate extended-release injectable suspension (firstsuspension), comprising administering in a deltoid muscle of the patienta re-initiation loading dose of a second paliperidone palmitateextended-release injectable suspension (second suspension) at a timethat is more than six months and three weeks after administration of thefirst dose of the first suspension but less than seven to nine months,e.g. less than eight months, after administration of said first dose ofthe first suspension; and administering in a deltoid or gluteal muscleof the patient a maintenance dose of the first suspension at a time thatis about one month (±7 days) after administering the re-initiationloading dose of the second suspension. In one embodiment, there-initiation loading dose of the second suspension and the maintenancedose of the first suspension are selected based on the first dose of thefirst suspension as shown below in Table 1, with the administration ofthe first suspension preferably in a gluteal muscle of the patient:

TABLE 1 Re-initiation First dose loading dose Maintenance of first ofsecond dose of first suspension suspension suspension 1092 mg 156 mg1092 mg 1560 mg 234 mg 1560 mg

To the extent a different dosing window is prescribed, the samere-initiation dosing regimen noted above may be implemented but adjustedbased on the outer dosing window parameter. For example, if the dosingwindow was up to 1 week earlier and up to 2 weeks after the targetinjection date, the re-initiation loading dose of the second suspensionwould be administered at a time that is more than six months and twoweeks after administration of the first dose of the first suspension butless than seven to nine months, e.g. less than eight months, afteradministration of said first dose of the first suspension.

Other re-initiation regimens are based on a missed dose of seven to ninemonths and up to and including ten to fourteen months after the lastinjection. For example, the disclosure includes administeringpaliperidone palmitate to a patient in need thereof who has beenadministered a first dose of a first paliperidone palmitateextended-release injectable suspension (first suspension), comprisingadministering to a deltoid muscle of the patient a first re-initiationloading dose of 156 mg paliperidone palmitate of a second paliperidonepalmitate extended-release injectable suspension (second suspension) ata time that is from seven to nine months, e.g. from eight months, up toand including ten to fourteen months, e.g. up to and including elevenmonths, after administration of the first dose of the first suspension;administering in a deltoid muscle of the patient a second re-initiationloading dose of 156 mg paliperidone palmitate of the second suspensionon about day 8 (±4 days) after administering the first re-initiationloading dose of the second suspension; and administering in a deltoid orgluteal muscle of the patient from about 1092 mg to about 1560 mgpaliperidone palmitate of a maintenance dose of the first suspensionabout one month (±7 days) after administering the second re-initiationloading dose of the second suspension. In one embodiment, the first doseof the first suspension is about 1092 mg paliperidone palmitate and themaintenance dose of the first suspension is about 1092 mg paliperidonepalmitate. In another embodiment, the first dose of the first suspensionis about 1560 mg paliperidone palmitate and the maintenance dose of thefirst suspension is about 1560 mg paliperidone palmitate. In preferredembodiments, the administration of the first suspension is in a glutealmuscle of the patient.

Other re-initiation regimens are based on a missed dose of more than tento fourteen months after the last injection. For example, the disclosureincludes administering paliperidone palmitate to a patient in needthereof who has been administered a first dose of a first paliperidonepalmitate extended-release injectable suspension (first suspension),comprising (1) administering in a deltoid muscle of the patient a firstre-initiation loading dose of 234 mg paliperidone palmitate of a secondpaliperidone palmitate extended-release injectable suspension (secondsuspension) at a time that is more than ten to fourteen months, e.g.more than eleven months, after administration of the first dose of thefirst suspension; (2) administering in a deltoid muscle of the patient asecond re-initiation loading dose of 156 mg paliperidone palmitate ofthe second suspension on about day 8 (±4 days) after administering thefirst re-initiation loading dose of the second suspension; (3)administering in a deltoid or gluteal muscle of the patient a firstre-initiation maintenance dose of 39 mg to about 234 mg paliperidonepalmitate of the second suspension about one month (±7 days) afteradministering the second re-initiation loading dose; (4) administeringin a deltoid or gluteal muscle of the patient a second re-initiationmaintenance dose of from about 39 mg to about 234 mg paliperidonepalmitate of the second suspension about one month (±7 days) afteradministering the first re-initiation maintenance dose of the secondsuspension; (5) administering in a deltoid or gluteal muscle of thepatient a third re-initiation maintenance dose of from about 39 mg toabout 234 mg paliperidone palmitate of the second suspension about onemonth (±7 days) after administering the second re-initiation maintenancedose of the second suspension; and (6) administering in a deltoid orgluteal muscle of the patient from about 1092 mg to about 1560 mgpaliperidone palmitate of a maintenance dose of the first suspensionabout one month (±7 days) after administering the third re-initiationmaintenance dose of the second suspension. Preferably, the firstsuspension is administered in a gluteal muscle. In one embodiment, thefirst dose of the first suspension is about 1092 mg paliperidonepalmitate and the maintenance dose of the first suspension is about 1092mg paliperidone palmitate. In another embodiment, the first dose of thefirst suspension is about 1560 mg paliperidone palmitate and themaintenance dose of the first suspension is about 1560 mg paliperidonepalmitate. In other embodiments, the second and third re-initiationmaintenance doses of second suspension are the same. Additionalre-initiation maintenance doses may be administered in one-month (±7days) intervals before the maintenance dose of the first suspension(e.g. a fourth re-initiation maintenance dose, a fifth re-initiationmaintenance dose, etc.). In certain embodiments, the re-initiationmaintenance doses of paliperidone palmitate are from about 156 to about234 mg. With respect to any of the re-initiation regimens, following themaintenance dose of the first suspension, the first suspension istypically administered in six-month intervals as noted herein.

In particular embodiments, the first suspension is PP6M and the secondsuspension is PP1M. Exemplary re-initiation regimens based on PP1M andPP6M are further disclosed in Example 8. A goal of a re-initiationregimen is to achieve a quick return to paliperidone plasmaconcentrations as before the missed dose without creating an overshootdue to the applied re-initiation regimen. It should be recognized thatthe methods do not contemplate intervening doses of paliperidonepalmitate between the enumerated doses of the missed dosing regimensdescribed herein, e.g., between the first dose and the re-initiationloading dose.

Another aspect of the present disclosure is an observed effect forlonger acting paliperidone palmitate treatments to improve blood lipidlevels, specifically fasting low density lipoprotein (LDL), fastingtriglycerides, fasting total cholesterol, or fasting high densitylipoprotein (HDL), or combinations thereof, in a patient population forwhich most treatments cause increase in cardiovascular risk factorsincluding increased or decreased blood lipid levels. In particular, ithas been found that transitioning patients who have been adequatelytreated with PP1M or PP3M to PP6M can mitigate (i.e., reduce, stop, orpotentially partially reverse) an adverse change of relevant bloodlipids while maintaining good pharmacological efficacy and maintainingrelapse prevention. In some embodiments, the adverse lipid levels arepaliperidone-induced, but also may be due to indirect mechanisms, suchas weight gain. In one embodiment, the adverse change in blood lipidprofile is paliperidone induced.

As a result, the present disclosure fulfills an unmet medical need forpatients with lipid abnormalities who are in need of long-term symptomprotection (and therefore antipsychotic treatment), but for whom acontinuous long-term treatment has metabolic effects which increase riskfactors for higher morbidity and mortality (e.g. due to cardiovasculardisease). The PP6M formulation and regimen disclosed herein allows forimprovement in blood lipid levels, specifically fasting LDL, fastingtriglycerides, fasting total cholesterol, or fasting HDL, orcombinations thereof, while providing the same efficacy compared toother paliperidone or paliperidone palmitate formulations (e.g. PP1M orPP3M).

In one embodiment, the disclosure provides methods for mitigatingadverse changes in blood lipid levels of a patient in need thereof whohas been treated with a paliperidone palmitate extended-releaseinjectable suspension at either one-month intervals (PP1M) orthree-month intervals (PP3M), comprising transitioning the patient to apaliperidone palmitate extended-release injectable suspension having asix month dosing interval (PP6M). The transition is typicallyaccomplished by administering to the patient a last dose of the PP1M orthe PP3M and then administering an initial dose of the PP6M. In oneembodiment, the transition is accomplished by administering to thepatient a last dose of PP1M and then administering an initial dose ofPP6M. In one embodiment, the transition is accomplished by administeringto the patient a last dose of PP3M and then administering an initialdose of PP6M. In a more particular embodiment, the transition isaccomplished by administering to the patient a last dose of PP3M andthen administering an initial dose of PP6M. In certain embodiments, thepatient has been treated with the PP1M for at least four months, atleast five months, or at least six months. In one embodiment, thepatient has been treated with the PP1M for at least four months. In oneembodiment, the patient has been treated with the PP1M for at least fivemonths. In one embodiment, the patient has been treated with the PP1Mfor at least six months. In other embodiments, the patient has beentreated with the PP3M for at least one 3-month interval, at least two3-month intervals, or at least three 3-month intervals. In oneembodiment, the patient has been treated with the PP3M for at least one3-month interval. In one embodiment, the patient has been treated withthe PP3M for at least two 3-month intervals. In one embodiment, thepatient has been treated with the PP3M for at least three 3-monthintervals. In one embodiment, the patient is in need of treatment for apsychotic disorder optionally selected from schizophrenia and/orschizoaffective disorder or bipolar disorder. In one embodiment, thepatient is in need of treatment for schizophrenia.

In one embodiment, the disclosure provides methods for mitigatingadverse changes in blood lipid levels during the treatment of apsychotic disorder in a patient in need thereof who has been treatedwith a paliperidone palmitate extended-release injectable suspension ateither one-month intervals (PP1M) or three-month intervals (PP3M),comprising transitioning the patient to a paliperidone palmitateextended-release injectable suspension having a six month dosinginterval (PP6M). The transition is typically accomplished byadministering to the patient a last dose of the PP1M or the PP3M andthen administering an initial dose of the PP6M. In one embodiment, thetransition is accomplished by administering to the patient a last doseof PP1M and then administering an initial dose of PP6M. In oneembodiment, the transition is accomplished by administering to thepatient a last dose of PP3M and then administering an initial dose ofPP6M. In certain embodiments, the patient has been treated with the PP1Mfor at least four months, at least five months, or at least six months.In one embodiment, the patient has been treated with the PP1M for atleast four months. In one embodiment, the patient has been treated withthe PP1M for at least five months. In one embodiment, the patient hasbeen treated with the PP1M for at least six months. In otherembodiments, the patient has been treated with the PP3M for at least one3-month interval, at least two 3-month intervals, or at least three3-month intervals. In one embodiment, the patient has been treated withthe PP3M for at least one 3-month interval. In one embodiment, thepatient has been treated with the PP3M for at least two 3-monthintervals. In one embodiment, the patient has been treated with the PP3Mfor at least three 3-month intervals. In one embodiment, the psychoticdisorder is selected from schizophrenia and/or schizoaffective disorderor bipolar disorder. In one embodiment, the psychotic disorder isschizophrenia.

In embodiments where the patient has been treated with PP1M, the initialdose of PP6M is administered about one month (±7 days) after the lastdose of the PP1M is administered. Typically, when the last dose of thePP1M is about 156 mg paliperidone palmitate, the initial dose of PP6M isabout 1092 mg paliperidone palmitate. In other embodiments, when thelast dose of the PP1M is about 234 mg paliperidone palmitate, theinitial dose of PP6M is about 1560 mg paliperidone palmitate.

In embodiments where the patient has been treated with PP3M, the initialdose of PP6M is administered about three months (±14 days) after thelast dose of the PP1M is administered. Typically, when the last dose ofthe PP3M is about 546 mg paliperidone palmitate, the initial dose ofPP6M is about 1092 mg paliperidone palmitate. In other embodiments, whenthe last dose of the PP3M is about 819 mg paliperidone palmitate, theinitial dose of PP6M is about 1560 mg paliperidone palmitate.

Following the initial dose of the PP6M, the PP6M is administered insix-month intervals as noted herein.

In one embodiment, the methods disclosed herein further compriseadministering to the patient at least one subsequent dose of PP6M up totwo weeks before or three weeks after a time that is six months afterthe administration of the initial dose of PP6M.

Further, the methods have particular relevance for patients sufferingfrom metabolic symptoms prior to the transition to the PP6M. In oneembodiment, the patient is a patient suffering from one or moremetabolic symptoms prior to the transition to PP6M. Those metabolicsymptoms can include, for example, obesity, high blood pressure, orinsulin resistance, or combinations thereof. In one embodiment, themetabolic symptoms are obesity, high blood pressure, or insulinresistance, or a combination thereof. In one embodiment, the metabolicsyndrome is obesity. In one embodiment, the metabolic syndrome is highblood pressure. In one embodiment, the metabolic syndrome is insulinresistance.

High blood triglycerides and low levels of HDL cholesterol together withthe previously mentioned factors can lead to a metabolic syndrome. Ametabolic syndrome is associated with higher risk of diabetes, stroke,and/or heart disease with a long-term increase in mortality of thisvulnerable population. The beneficial effects of the longer-actingpaliperidone palmitate formulation can potentially help to prevent thesenegative long-term cardiovascular outcomes and help to maintain apatient's long-term healthy medical condition, functionality, andquality-of-life by positively effecting common cardiovascular riskfactors in the course of an antipsychotic pharmacological treatment.

In certain embodiments, at the time of the last dose of PP1M or PP3M,the patient has a body mass index (BMI) of less than 25; 25 to less than30; or greater than or equal to 30. In one embodiment, at the time ofthe last dose of PP1M or PP3M, the patient has a body mass index (BMI)of less than 25. In one embodiment, at the time of the last dose of PP1Mor PP3M, the patient has a body mass index (BMI) of 25 to less than 30.In one embodiment, at the time of the last dose of PP1M or PP3M, thepatient has a body mass index (BMI) of greater than or equal to 30. Inone embodiment, at the time of the last dose of PP1M, the patient has abody mass index (BMI) of less than 25. In one embodiment, at the time ofthe last dose of PP1M, the patient has a body mass index (BMI) of 25 toless than 30. In one embodiment, at the time of the last dose of PP1M,the patient has a body mass index (BMI) of greater than or equal to 30.In one embodiment, at the time of the last dose of PP3M, the patient hasa body mass index (BMI) of less than 25. In one embodiment, at the timeof the last dose of PP3M, the patient has a body mass index (BMI) of 25to less than 30. In one embodiment, at the time of the last dose ofPP3M, the patient has a body mass index (BMI) of greater than or equalto 30.

Unless otherwise noted, the term “mitigating adverse changes in bloodlipid levels” refers to preventing the patient's lipid levels frombecoming worse relative to such levels in the absence of transitioningthe patient to the PP6M. In other words, the methods avoid worsening ofan increase or decrease in blood lipid levels that the patient wouldexperience being maintained on PP1M or PP3M treatment. In particularembodiments, the methods avoid worsening of a paliperidone-inducedincrease or decrease in blood lipid levels that the patient wouldexperience being maintained on PP1M or PP3M treatment, and, inparticular, PP3M treatment.

Typically, the benefits of the methods are compared to an increase ofLDL, fasting triglycerides, or fasting total cholesterol, or a decreaseof HDL, or combinations thereof, that the patient would have experiencedbeing maintained on PP1M or PP3M treatment. For cholesterol, LDL, andtriglycerides, an increase in value is considered a worsening, whereasfor HDL a decrease in value is considered a worsening. Accordingly, forcholesterol, LDL and triglycerides, avoiding a worsening encompassesavoiding an increase, or experiencing less of an increase, as comparedto the levels that the patient would experience in the absence of atransition to PP6M. It could also encompass maintaining such valuesbelow the level that would be experienced by the patient in the absenceof the transition to PP6M. Similarly, for those lipid values where adecrease is considered worsening, such as HDL, avoiding a worseningencompasses avoiding a decrease, or experiencing less of a decrease,compared to the lipid level of the patient in the absence of thetransition to PP6M. It could also encompass maintaining the HDL at alevel above the level experienced by the patient in the absence of thetransition.

In one embodiment, the adverse change is an adverse change in fastinglow density lipoprotein (LDL), fasting triglycerides, fasting totalcholesterol, or fasting high density lipoprotein (HDL), or a combinationthereof. In one embodiment, the adverse change is an adverse change infasting low density lipoprotein (LDL). In one embodiment, the adversechange is an adverse change in fasting triglycerides. In one embodiment,the adverse change is an adverse change in fasting total cholesterol. Inone embodiment, the adverse change is an adverse change in fasting highdensity lipoprotein (HDL).

In one embodiment, the adverse change is an increase in fasting lowdensity lipoprotein (LDL), an increase in fasting triglycerides, anincrease in fasting total cholesterol, or a decrease in fasting highdensity lipoprotein (HDL), or a combination thereof. In one embodiment,the adverse change is an increase in fasting low density lipoprotein(LDL). In one embodiment, the adverse change is an increase in fastingtriglycerides. In one embodiment, the adverse change is an increase infasting total cholesterol. In one embodiment, the adverse change is adecrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP1M or PP3M, thepatient has a body mass index (BMI) of less than 25 and the adversechange is an adverse change in fasting low density lipoprotein (LDL),e.g., an increase in fasting low density lipoprotein (LDL). In oneembodiment, at the time of the last dose of PP1M or PP3M, the patienthas a body mass index (BMI) of less than 25 and the adverse change is anadverse change in fasting triglycerides, e.g., an increase in fastingtriglycerides. In one embodiment, at the time of the last dose of PP1Mor PP3M, the patient has a body mass index (BMI) of less than 25 and theadverse change is an adverse change in fasting cholesterol, e.g., anincrease in fasting cholesterol. In one embodiment, at the time of thelast dose of PP1M or PP3M, the patient has a body mass index (BMI) ofless than 25 and the adverse change is an adverse change in fasting highdensity lipoprotein (HDL), e.g., a decrease in fasting high densitylipoprotein (HDL).

In one embodiment, at the time of the last dose of PP1M or PP3M, thepatient has a body mass index (BMI) of 25 to less than 30 and theadverse change is an adverse change in fasting low density lipoprotein(LDL), e.g., an increase in fasting low density lipoprotein (LDL). Inone embodiment, at the time of the last dose of PP1M or PP3M, thepatient has a body mass index (BMI) of 25 to less than 30 and theadverse change is an adverse change in fasting triglycerides, e.g., anincrease in fasting triglycerides. In one embodiment, at the time of thelast dose of PP1M or PP3M, the patient has a body mass index (BMI) of 25to less than 30 and the adverse change is an adverse change in fastingcholesterol, e.g., an increase in fasting cholesterol. In oneembodiment, at the time of the last dose of PP1M or PP3M, the patienthas a body mass index (BMI) of 25 to less than 30 and the adverse changeis an adverse change in fasting high density lipoprotein (HDL), e.g., adecrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP1M or PP3M, thepatient has a body mass index (BMI) of greater than or equal to 30 andthe adverse change is an adverse change in fasting low densitylipoprotein (LDL), e.g., an increase in fasting low density lipoprotein(LDL). In one embodiment, at the time of the last dose of PP1M or PP3M,the patient has a body mass index (BMI) of greater than or equal to 30and the adverse change is an adverse change in fasting triglycerides,e.g., an increase in fasting triglycerides. In one embodiment, at thetime of the last dose of PP1M or PP3M, the patient has a body mass index(BMI) of greater than or equal to 30 and the adverse change is anadverse change in fasting cholesterol, e.g., an increase in fastingcholesterol. In one embodiment, at the time of the last dose of PP1M orPP3M, the patient has a body mass index (BMI) of greater than or equalto 30 and the adverse change is an adverse change in fasting highdensity lipoprotein (HDL), e.g., a decrease in fasting high densitylipoprotein (HDL).

In one embodiment, at the time of the last dose of PP1M, the patient hasa body mass index (BMI) of less than 25 and the adverse change is anadverse change in fasting low density lipoprotein (LDL), e.g., anincrease in fasting low density lipoprotein (LDL). In one embodiment, atthe time of the last dose of PP1M, the patient has a body mass index(BMI) of less than 25 and the adverse change is an adverse change infasting triglycerides, e.g., an increase in fasting triglycerides. Inone embodiment, at the time of the last dose of PP1M, the patient has abody mass index (BMI) of less than 25 and the adverse change is anadverse change in fasting cholesterol, e.g., an increase in fastingcholesterol. In one embodiment, at the time of the last dose of PP1M,the patient has a body mass index (BMI) of less than 25 and the adversechange is an adverse change in fasting high density lipoprotein (HDL),e.g., a decrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP1M, the patient hasa body mass index (BMI) of 25 to less than 30 and the adverse change isan adverse change in fasting low density lipoprotein (LDL), e.g., anincrease in fasting low density lipoprotein (LDL). In one embodiment, atthe time of the last dose of PP1M, the patient has a body mass index(BMI) of 25 to less than 30 and the adverse change is an adverse changein fasting triglycerides, e.g., an increase in fasting triglycerides. Inone embodiment, at the time of the last dose of PP1M, the patient has abody mass index (BMI) of 25 to less than 30 and the adverse change is anadverse change in fasting cholesterol, e.g., an increase in fastingcholesterol. In one embodiment, at the time of the last dose of PP1M,the patient has a body mass index (BMI) of 25 to less than 30 and theadverse change is an adverse change in fasting high density lipoprotein(HDL), e.g., a decrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP1M, the patient hasa body mass index (BMI) of greater than or equal to 30 and the adversechange is an adverse change in fasting low density lipoprotein (LDL),e.g., an increase in fasting low density lipoprotein (LDL). In oneembodiment, at the time of the last dose of PP1M, the patient has a bodymass index (BMI) of greater than or equal to 30 and the adverse changeis an adverse change in fasting triglycerides, e.g., an increase infasting triglycerides. In one embodiment, at the time of the last doseof PP1M, the patient has a body mass index (BMI) of greater than orequal to 30 and the adverse change is an adverse change in fastingcholesterol, e.g., an increase in fasting cholesterol. In oneembodiment, at the time of the last dose of PP1M, the patient has a bodymass index (BMI) of greater than or equal to 30 and the adverse changeis an adverse change in fasting high density lipoprotein (HDL), e.g., adecrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP3M, the patient hasa body mass index (BMI) of less than 25 and the adverse change is anadverse change in fasting low density lipoprotein (LDL), e.g., anincrease in fasting low density lipoprotein (LDL). In one embodiment, atthe time of the last dose of PP3M, the patient has a body mass index(BMI) of less than 25 and the adverse change is an adverse change infasting triglycerides, e.g., an increase in fasting triglycerides. Inone embodiment, at the time of the last dose of PP3M, the patient has abody mass index (BMI) of less than 25 and the adverse change is anadverse change in fasting cholesterol, e.g., an increase in fastingcholesterol. In one embodiment, at the time of the last dose of PP3M,the patient has a body mass index (BMI) of less than 25 and the adversechange is an adverse change in fasting high density lipoprotein (HDL),e.g., a decrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP3M, the patient hasa body mass index (BMI) of 25 to less than 30 and the adverse change isan adverse change in fasting low density lipoprotein (LDL), e.g., anincrease in fasting low density lipoprotein (LDL). In one embodiment, atthe time of the last dose of PP3M, the patient has a body mass index(BMI) of 25 to less than 30 and the adverse change is an adverse changein fasting triglycerides, e.g., an increase in fasting triglycerides. Inone embodiment, at the time of the last dose of PP3M, the patient has abody mass index (BMI) of 25 to less than 30 and the adverse change is anadverse change in fasting cholesterol, e.g., an increase in fastingcholesterol. In one embodiment, at the time of the last dose of PP3M,the patient has a body mass index (BMI) of 25 to less than 30 and theadverse change is an adverse change in fasting high density lipoprotein(HDL), e.g., a decrease in fasting high density lipoprotein (HDL).

In one embodiment, at the time of the last dose of PP3M, the patient hasa body mass index (BMI) of greater than or equal to 30 and the adversechange is an adverse change in fasting low density lipoprotein (LDL),e.g., an increase in fasting low density lipoprotein (LDL). In oneembodiment, at the time of the last dose of PP3M, the patient has a bodymass index (BMI) of greater than or equal to 30 and the adverse changeis an adverse change in fasting triglycerides, e.g., an increase infasting triglycerides. In one embodiment, at the time of the last doseof PP3M, the patient has a body mass index (BMI) of greater than orequal to 30 and the adverse change is an adverse change in fastingcholesterol, e.g., an increase in fasting cholesterol. In oneembodiment, at the time of the last dose of PP3M, the patient has a bodymass index (BMI) of greater than or equal to 30 and the adverse changeis an adverse change in fasting high density lipoprotein (HDL), e.g., adecrease in fasting high density lipoprotein (HDL).

It can also be helpful to understand if patients shift from one categoryto another in terms of lipid risk. For example, typical categoriesinclude Fasting Cholesterol (mg/dL): <200 mg/dL to >=240 mg/dL; FastingHDL Cholesterol (mg/dL): >=40 mg/dL to <40 mg/dL; Fasting LDLCholesterol (mg/dL): <100 mg/dL to >=160 mg/dL; and FastingTriglycerides (mg/dL): <150 mg/dL to >=200 mg/dL. For fastingcholesterol, LDL, and fasting triglycerides, an optimal value is belowthe beginning of the above-noted range, whereas for fasting HDL, anoptimal value would be above the beginning of the range. The methods oftransitioning a patient from PP1M or PP3M to PP6M can result in thepatient avoiding a shift from baseline to a higher risk category(baseline refers to values at the time of the initial dose of the PP6M).For example, in one embodiment, the disclosure provides methods foravoiding a shift from baseline to a higher lipid risk category in apatient by transitioning the patient from PP1M or PP3M to PP6M, asdescribed herein. In one embodiment, the disclosure provides methods foravoiding a shift from baseline to a higher lipid risk category in apatient by transitioning the patient from PP3M to PP6M, as describedherein. In one embodiment, the disclosure provides methods for avoidinga shift from baseline to a higher lipid risk category in a patient bytransitioning the patient from PP1M to PP6M, as described herein. In oneembodiment, the transition in a lipid risk category is a transition infasting cholesterol category, a fasting LDL cholesterol category, afasting HDL cholesterol category, or a fasting triglycerides category.In one embodiment, the transition in a lipid risk category is atransition in fasting cholesterol category, e.g., a transition from <200mg/dL to >=240 mg/dL. In one embodiment, the transition in a lipid riskcategory is a transition in fasting LDL cholesterol category, e.g., atransition from <100 mg/dL to >=160 mg/dL. In one embodiment, thetransition in a lipid risk category is a transition in fasting HDLcholesterol category, e.g. a transition from >=40 mg/dL to <40 mg/dL. Inone embodiment, the transition in a lipid risk category is a transitionin fasting triglycerides category, e.g. a transition from <150 mg/dLto >=200 mg/dL. For the avoidance of doubt, all of the embodimentsdescribed above in relation to methods for mitigating an adverse changein blood lipid profile apply equally to the embodiments relating tomethods for avoiding a shift from baseline to a higher lipid riskcategory, and vice versa.

In other aspects, the patient's lipid levels are assessed or determinedduring treatment with the PP1M or PP3M, at the time of the last dose ofthe PP1M or PP3M, at the time of the initial dose of PP6M, at subsequenttime points following the transition to PP6M, or a combination thereof.In other aspects, the patient's lipid levels are assessed or determinedduring treatment with the PP1M, at the time of the last dose of thePP1M, at the time of the initial dose of PP6M, at subsequent time pointsfollowing the transition to PP6M, or a combination thereof. In otheraspects, the patient's lipid levels are assessed or determined duringtreatment with the PP3M, at the time of the last dose of the PP3M, atthe time of the initial dose of PP6M, at subsequent time pointsfollowing the transition to PP6M, or a combination thereof. Theseassessments and their timing can help the patient and/or the health careprofessional determine how best to proceed with treatment and/or howbest to monitor results.

In one embodiment, the disclosure provides methods for mitigating therisk of diabetes, stroke, and/or heart disease in a patient in needthereof who has been treated with a paliperidone palmitateextended-release injectable suspension at either one-month intervals(PP1M) or three-month intervals (PP3M), comprising transitioning thepatient to a paliperidone palmitate extended-release injectablesuspension having a six month dosing interval (PP6M). The transition istypically accomplished by administering to the patient a last dose ofthe PP1M or the PP3M and then administering an initial dose of the PP6M.In one embodiment, the transition is accomplished by administering tothe patient a last dose of PP1M and then administering an initial doseof PP6M. In one embodiment, the transition is accomplished byadministering to the patient a last dose of PP3M and then administeringan initial dose of PP6M. In certain embodiments, the patient has beentreated with the PP1M for at least four months, at least five months, orat least six months. In one embodiment, the patient has been treatedwith the PP1M for at least four months. In one embodiment, the patienthas been treated with the PP1M for at least five months. In oneembodiment, the patient has been treated with the PP1M for at least sixmonths. In other embodiments, the patient has been treated with the PP3Mfor at least one 3-month interval, at least two 3-month intervals, or atleast three 3-month intervals. In one embodiment, the patient has beentreated with the PP3M for at least one 3-month interval. In oneembodiment, the patient has been treated with the PP3M for at least two3-month intervals. In one embodiment, the patient has been treated withthe PP3M for at least three 3-month intervals. In one embodiment, thepatient is in need of treatment for a psychotic disorder selected fromschizophrenia and/or schizoaffective disorder or bipolar disorder. Inone embodiment, the patient is in need of treatment for schizophrenia.In one embodiment, the mitigation of the risk of diabetes, stroke,and/or heart disease is attributable to mitigation of an adverse changein blood lipid profile. In one embodiment, the method is a method formitigating the risk of diabetes. In one embodiment, the method is amethod for mitigating the risk of stroke. In one embodiment, the methodis a method for mitigating the risk of heart disease.

In one embodiment, the disclosure provides methods for mitigating therisk of diabetes, stroke, and/or heart disease during the treatment of apsychotic disorder selected from schizophrenia and/or schizoaffectivedisorder or bipolar disorder in a patient in need thereof who has beentreated with a paliperidone palmitate extended-release injectablesuspension at either one-month intervals (PP1M) or three-month intervals(PP3M), comprising transitioning the patient to a paliperidone palmitateextended-release injectable suspension having a six month dosinginterval (PP6M). In one embodiment, the psychotic disorder isschizophrenia. The transition is typically accomplished by administeringto the patient a last dose of the PP1M or the PP3M and thenadministering an initial dose of the PP6M. In one embodiment, thetransition is accomplished by administering to the patient a last doseof PP1M and then administering an initial dose of PP6M. In oneembodiment, the transition is accomplished by administering to thepatient a last dose of PP3M and then administering an initial dose ofPP6M. In certain embodiments, the patient has been treated with the PP1Mfor at least four months, at least five months, or at least six months.In one embodiment, the patient has been treated with the PP1M for atleast four months. In one embodiment, the patient has been treated withthe PP1M for at least five months. In one embodiment, the patient hasbeen treated with the PP1M for at least six months. In otherembodiments, the patient has been treated with the PP3M for at least one3-month interval, at least two 3-month intervals, or at least three3-month intervals. In one embodiment, the patient has been treated withthe PP3M for at least one 3-month interval. In one embodiment, thepatient has been treated with the PP3M for at least two 3-monthintervals. In one embodiment, the patient has been treated with the PP3Mfor at least three 3-month intervals. In one embodiment, the mitigationof the risk of diabetes, stroke, and/or heart disease is attributable tomitigation of an adverse change in blood lipid profile. In oneembodiment, the method is a method for mitigating the risk of diabetes.In one embodiment, the method is a method for mitigating the risk ofstroke. In one embodiment, the method is a method for mitigating therisk of heart disease.

For the avoidance of doubt, all of the embodiments described above inrelation to methods for mitigating an adverse change in blood lipidprofile and for methods for avoiding a shift from baseline to a higherlipid risk category apply equally to the embodiments relating to methodsfor mitigating the risk of diabetes, stroke, and/or heart disease, andvice versa.

Paliperidone Palmitate Formulations

Paliperidone esters are antipsychotic agents belonging to the chemicalclass of benzisoxazole derivatives, which contains a racemic mixture of(+)- and (−)-paliperidone, which are described in U.S. Pat. No.5,254,556 (incorporated herein by reference). The chemical name forpaliperidone palmitate is(±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-c]pyrimidin-9-ylhexadecanoate. The structural formula is:

Paliperidone esters may be formulated with pharmaceutical excipientsinto injectable dosage forms as described in U.S. Pat. Nos. 5,254,556and 6,077,843 both of which are incorporated herein by reference.Injectable formulations may be formulated in aqueous carriers.

As described in U.S. Pat. No. 9,439,906, incorporated herein byreference, a one-month aqueous formulation is a nano particle suspensionwherein the nano particles have average sizes of less than about 2,000nm to about 100 nm. For example, the nano particles have an averageparticle size (d50) of from about 1,600 nm to about 400 nm, or fromabout 1,400 nm to about 900 nm. The d90 is less than about 5,000 nm, orless than about 4,400 nm. The d10 is from about 300 nm to about 600 nm.As used herein, d10: the portion of particles with diameters smallerthan this value is 10%; d50: the portion of particles with diameterssmaller than this value are 50%; d90: the portion of particles withdiameters smaller than this value is 90%; when measured by art-knownconventional techniques, such as sedimentation field flow fractionation,photon correlation spectroscopy or disk centrifugation.

In certain embodiments, a three-month (PP3M) formulation has averageparticle sizes of less than about 20 μm to about 1 μm. In otherembodiments, the particles have an average particle size (d50) of fromabout 5 μm to about 15 μm; from about 3 μm to about 10 μm; or from about5 μm to about 9 μm. The d90 is about 50 μm; from about 10 μm to about 30μm; or from about 10 μm to about 20 μm. The d10 is from about 1 μm toabout 10 μm, or from about 1 μm to about 5 μm.

In certain embodiments, a six-month (PP6M) formulation has averageparticle sizes of less than about 30 μm to about 1 μm; or about 20 μm toabout 1 μm. In other embodiments, the particles have an average particlesize (d50) of from about 3 μm to about 25 μm; from about 5 μm to about15 μm; from about 3 μm to about 10 μm; or from about 5 μm to about 9 μm.The d90 is 60 μm; or about 50 μm; from about 10 μm to about 30 μm; orfrom about 10 μm to about 20 μm. The d10 is from about 1 μm to about 15μm; from about 1 μm to about 10 μm; or from about 1 μm to about 5 μm.

Suitable aqueous nanoparticle formulations are described in U.S. Pat.No. 6,555,544 which is incorporated herein by reference. In someembodiments, the formulation comprises micro particles, a surfactant, asuspending agent, and optionally one or more additional ingredientsselected from the group consisting of preservatives, buffers and anisotonizing agent.

Useful surface modifiers for paliperidone palmitate formulations arebelieved to include those that physically adhere to the surface of theactive agent but do not chemically bond thereto. Suitable surfacemodifiers can preferably be selected from known organic and inorganicpharmaceutical excipients. Such excipients include various polymers, lowmolecular weight oligomers, natural products and surfactants. Preferredsurface modifiers include nonionic and anionic surfactants.Representative examples of excipients include gelatin, casein, lecithin(phosphatides), gum acacia, cholesterol, tragacanth, stearic acid,benzalkonium chloride, calcium stearate, glyceryl monostearate,cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitanfatty acid esters, e.g., the commercially available TWEENS™,polyethylene glycols, polyoxyethylene stearates, colloidal silicondioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose phtalate, noncrystalline cellulose,magnesium aluminate silicate, triethanolamine, polyvinyl alcohol (PVA),poloxamers, tyloxapol and polyvinylpyrrolidone (PVP). Most of theseexcipients are described in detail in the Handbook of PharmaceuticalExcipients, published jointly by the American Pharmaceutical Associationand The Pharmaceutical Society of Great Britain, the PharmaceuticalPress, 1986. The surface modifiers are commercially available and/or canbe prepared by techniques known in the art. Two or more surfacemodifiers can be used in combination.

Particularly preferred surface modifiers include polyvinylpyrrolidone;tyloxapol; poloxamers, such as PLURONIC™ F68, F108 and F127 which areblock copolymers of ethylene oxide and propylene oxide available fromBASF; poloxamines, such as TETRONIC™ 908 (T908) which is atetrafunctional block copolymer derived from sequential addition ofethylene oxide and propylene oxide to ethylenediamine available fromBASF; dextran; lecithin; Aerosol OT™ (AOT) which is a dioctyl ester ofsodium sulfosuccinic acid available from Cytec Industries; DUPONOL™ Pwhich is a sodium lauryl sulfate available from DuPont; TRITON™ X-200which is an alkyl aryl polyether sulfonate available from Rohm and Haas;TWEEN™ 20, 40, 60 and 80 which are polyoxyethylene sorbitan fatty acidesters available from ICI Speciality Chemicals; SPAN™ 20, 40, 60 and 80which are sorbitan esters of fatty acids; ARLACEL™ 20, 40, 60 and 80which are sorbitan esters of fatty acids available from Hercules, Inc.;CARBOWAX™ 3550 and 934 which are polyethylene glycols available fromUnion Carbide; CRODESTA™ F110 which is a mixture of sucrose stearate andsucrose distearate available from Croda Inc.; CRODESTA™ SL-40 which isavailable from Croda, Inc.; hexyldecyl trimethyl ammonium chloride(CTAC); bovine serum albumin and SA9OHCO which isC₁₈H₁₇CH₂(CON(CH₃)CH₂(CHOH)₄CH₂OH)₂. The surface modifiers which havebeen found to be particularly useful include tyloxapol and a poloxamer,preferably, Pluronic™ F108 and Pluronic™ F68.

Pluronic™ F108 corresponds to poloxamer 338 and is the polyoxyethylene,polyoxypropylene block copolymer that conforms generally to the formulaHO[CH₂CH₂O]_(x)[CH(CH₃)CH₂O]_(y)[CH₂CH₂O]_(z)H in which the averagevalues of x, y and z are respectively 128, 54 and 128. Other commercialnames of poloxamer 338 are Hodag NONIONIC™ 1108-F available from Hodag,and SYNPERONIC™ PE/F108 available from ICI Americas.

The optimal relative amount of paliperidone palmitate and the surfacemodifier depends on various parameters. The optimal amount of thesurface modifier can depend, for example, upon the particular surfacemodifier selected, the critical micelle concentration of the surfacemodifier if it forms micelles, the surface area of the antipsychoticagent, etc. The specific surface modifier preferably is present in anamount of about 0.1 to about 1 mg per square meter surface area of thepaliperidone palmitate. It is preferred in the case of paliperidonepalmitate (9-hydroxyrisperidone palmitate) to use PLURONIC™ F108 as asurface modifier, a relative amount (w/w) of both ingredients ofapproximately 6:1 is preferred.

The particles of this invention can be prepared by a method comprisingthe steps of dispersing paliperidone palmitate in a liquid dispersionmedium and applying mechanical means in the presence of grinding mediato reduce the particle size of the antipsychotic agent to an effectiveaverage particle size. The particles can be reduced in size in thepresence of a surface modifier. Alternatively, the particles can becontacted with a surface modifier after attrition.

A general procedure for preparing the particles described hereinincludes (a) obtaining paliperidone palmitate; (b) adding thepaliperidone palmitate to a liquid medium to form a premix; and (c)subjecting the premix to mechanical means in the presence of a grindingmedium to reduce the effective average particle size.

The paliperidone palmitate may be prepared using techniques known in theart. It is preferred that the particle size of the paliperidonepalmitate be less than about 100 μm as determined by sieve analysis. Ifthe particle size of the paliperidone palmitate is greater than about100 then it is preferred that the particles of paliperidone palmitate bereduced in size to less than 100 μm.

The paliperidone palmitate can then be added to a liquid medium in whichit is essentially insoluble to form a premix. The concentration ofpaliperidone palmitate in the liquid medium (weight by weightpercentage) can vary widely and depends on the selected surface modifierand other factors. Suitable concentrations of paliperidone palmitate incompositions vary from about 0.1% to about 60%, preferably is from about0.5% to about 30%, and more preferably, is approximately 7% (w/v). ForPP1M, it is currently preferred to use a concentration of about 100 mgeq. of paliperidone per mL or about 156 mg of paliperidone palmitate permL. For PP3M, it is preferred to use a concentration of about 200 mg eq.of paliperidone per mL or about 312 mg of paliperidone palmitate per mL.For PP6M, it is preferred to use a concentration of about 200 mg eq. ofpaliperidone per mL or about 312 mg of paliperidone palmitate per mL.

A more preferred procedure involves the addition of a surface modifierto the premix prior to its subjection to mechanical means to reduce theeffective average particle size. The concentration of the surfacemodifier (weight by weight percentage) can vary from about 0.1% to about90%, preferably from about 0.5% to about 80%, and more preferably isapproximately 7% (w/v).

The premix can be used directly by subjecting it to mechanical means toreduce the effective average particle size in the dispersion to thedesired particle size. It is preferred that the premix be used directlywhen a ball mill is used for attrition. Alternatively, the antipsychoticagent and, optionally, the surface modifier, can be dispersed in theliquid medium using suitable agitation such as, for example, a rollermill or a Cowles type mixer, until a homogeneous dispersion is achieved.

The mechanical means applied to reduce the effective average particlesize of the antipsychotic conveniently can take the form of a dispersionmill. Suitable dispersion mills include a ball mill, an attritor mill, avibratory mill, a planetary mill, media mills—such as a sand mill and abead mill. A media mill is preferred due to the relatively shortermilling time required to provide the desired reduction in particle size.For media milling, in some embodiments, the apparent viscosity of thepremix preferably is anywhere between about 0.1 Pa·s and about 1 Pa·s.In some embodiments, for ball milling, the apparent viscosity of thepremix preferably is anywhere between about 1 mPa·s and about 100 mPa·s.

The grinding media for the particle size reduction step can be selectedfrom rigid media preferably spherical or particulate in form having anaverage size less than about 3 mm and, more preferably, less than about1 mm. Such media desirably can provide the particles of the inventionwith shorter processing times and impart less wear to the millingequipment. The selection of the material for the grinding media isbelieved not to be critical. However, about 95% ZrO stabilized withmagnesia, zirconium silicate, and glass grinding media provide particleswhich are acceptable for the preparation of pharmaceutical compositions.Further, other media, such as polymeric beads, stainless steel, titania,alumina and about 95% ZrO stabilized with yttrium, are useful. Preferredgrinding media have a density greater than about 2.5 g/cm³ and includeabout 95% ZrO stabilized with magnesia and polymeric beads.

The attrition time can vary widely and depends primarily upon theparticular mechanical means and processing conditions selected. Forrolling mills, processing times of up to two days or longer may berequired for smaller size particles.

The particles are typically reduced in size at a temperature which doesnot significantly degrade the antipsychotic agent. Processingtemperatures of less than about 30° C. to about 40° C. are ordinarilypreferred. If desired, the processing equipment may be cooled withconventional cooling equipment. The method is conveniently carried outunder conditions of ambient temperature and at processing pressureswhich are safe and effective for the milling process.

The surface modifier, if it was not present in the premix, is typicallyadded to the dispersion after attrition in an amount, for example, asdescribed for the premix above. Thereafter, the dispersion can be mixedby, for example, shaking vigorously. Optionally, the dispersion can besubjected to a sonication step using, for example, an ultrasonic powersupply.

Aqueous compositions according to the present invention convenientlyfurther comprise a suspending agent and a buffer, and optionally one ormore of a preservative and an isotonizing agent. Particular ingredientsmay function as two or more of these agents simultaneously, e.g. behavelike a preservative and a buffer, or behave like a buffer and anisotonizing agent.

Suitable suspending agents (also referred to as physical stabilizers)for use in the aqueous suspensions according to the present inventionare cellulose derivatives, e.g. methyl cellulose, sodium carboxymethylcellulose and hydroxypropyl methyl cellulose, polyvinylpyrrolidone,alginates, chitosan, dextrans, gelatin, polyethylene glycols,polyoxyethylene- and polyoxy-propylene ethers. Preferably sodiumcarboxymethyl cellulose is used in a concentration of about 0.5 to about2%, most preferably about 1% (w/v).

Suitable wetting agents preferred from the listed surfactant for use inthe aqueous suspensions according to the present invention arepolyoxyethylene derivatives of sorbitan esters, e.g. polysorbate 20 andpolysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers,sodium deoxycholate. Preferably polysorbate 20 is used in aconcentration of about 0.5% to about 3%, more preferably about 0.5% toabout 2%, most preferably about 1.1% (w/v).

Suitable buffering agents are salts of weak acids and should be used inamount sufficient to render the dispersion from about pH 6.0 to basic.Preferably, the pH is in a range of from about 6.0 to about 9.0; or inthe range of from about 6.0 to about 8.0; or about 6.5 to about 7.5. Forexample, the pH is in the range of about 6.0 to about 6.5; or from about6.5 to about 7.0; or from about 7.0 to about 7.5; or from about 7.5 toabout 8.0; or from about 8.0 to about 8.5; or from about 8.5 to about9.0. Particularly preferred is the use of a mixture of disodium hydrogenphosphate (anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogenphosphate monohydrate (typically about 0.6% (w/v)). This buffer alsorenders the dispersion isotonic and, in addition, less prone toflocculation of the ester suspended therein.

Preservatives are antimicrobials and anti-oxidants which can be selectedfrom the group consisting of benzoic acid, benzyl alcohol, butylatedhydroxyanisole, butylated hydroxytoluene, chlorbutol, a gallate, ahydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethoniumchloride, myristyl-gamma-piccolinium chloride, phenylmercuric acetateand thimerosal. In particular, it is benzyl alcohol which can be used ina concentration up to about 2% (w/v), preferably up to about 1.5% (w/v).

Isotonizing agents are, for example, sodium chloride, dextrose,mannitol, sorbitol, lactose, sodium sulfate. The suspensionsconveniently comprise from about 0% to about 10% (w/v) isotonizingagent. Mannitol may be used in a concentration from about 0% to about 7%more preferably, however, from about 1% to about 3% (w/v), especiallyfrom about 1.5% to about 2% (w/v) of one or more electrolytes are usedto render the suspension isotonic, apparently because ions help toprevent flocculation of the suspended ester. In particular, electrolytesof the buffer serve as isotonizing agent.

A particularly desirable feature for an injectable formulation relatesto the ease with which it can be administered. In particular such aninjection should be feasible using a needle as fine as possible in aspan of time which is as short as possible. This can be accomplishedwith the aqueous suspensions of the present invention by maintainingcertain viscosities that can be easily taken up in a syringe (e.g. froma vial) and injected through a fine needle. For example, a PP1Mviscosity is below about 75 mPa·s, or below about 60 mPa·s at roomtemperature, and a 23 G, 1 inch needle, or a 22 G, 1½ inch needle istypically used For PP3M, a 22 G, 1½ inch needle, or a 22 G, 1 inchneedle is typically used. And for PP6M, a 20 G, 1½ inch needle istypically used.

Ideally, aqueous suspensions according to the present invention willcomprise as much paliperidone palmitate as can be tolerated so as tokeep the injected volume to a minimum, and as little of the otheringredients as possible.

In particular for PP3M or PP6M, the composition comprises, or consistsessentially of, (a) from about 200 to about 500 mg/mL of paliperidonepalmitate; (b) from about 2 to about 25 mg/mL of wetting agent; (c) fromabout 2.5 to about 50 mg/mL of one or more buffering agents; (d) fromabout 25 to about 150 mg/mL of a suspending agent; (e) optionally up toabout 2% (w/v) preservatives; and (f) water q.s. ad 100%. Typically, thePP3M or PP6M composition has a pH of from about 6.0 to about 8.0,preferably about a pH of from 6.5 to about 7.5.

In other embodiments, for PP3M or PP6M, the composition comprises, orconsists essentially of, (a) from about 250 to about 400 mg/mL ofpaliperidone palmitate; (b) from about 5 to about 20 mg/mL of wettingagent; (c) from about 5 to about 25 mg/mL of one or more bufferingagents; (d) from about 50 to about 100 mg/mL of a suspending agent; (e)optionally up to about 2% (w/v) preservatives; and (f) water q.s. ad100%.

In other embodiments, for PP3M or PP6M, the composition comprises, orconsists essentially of, (a) from about 280 to about 350 mg/mL ofpaliperidone palmitate; (b) from about 8 to about 12 mg/mL of wettingagent; (c) from about 5 to about 15 mg/mL of one or more bufferingagents; (d) from about 65 to about 85 mg/mL of a suspending agent; (e)optionally up to about 2% (w/v) preservatives; and (f) water q.s. ad100%.

In certain embodiments, the active ingredient in PP3M or PP6M ispaliperidone palmitate (about 312 mg/mL). In certain embodiments, theinactive ingredients in PP3M or PP6M is polysorbate 20 (about 10 mg/mL),polyethylene glycol 4000 (about 75 mg/mL), citric acid monohydrate(about 7.5 mg/mL), sodium dihydrogen phosphate monohydrate (about 6mg/mL), sodium hydroxide (about 5.4 mg/mL) and water for injection. Anexemplified PP3M is disclosed in Example 2. An exemplified PP6M isdisclosed in Example 3.

In particular, a composition for PP1M will comprise, or consistessentially of, by weight based on the total volume of the composition:(a) from about 1% to 50% (w/v) of the paliperidone palmitate; (b) fromabout 0.1% to 5% (w/v) of a wetting agent; (c) one or more bufferingagents; (d) from about 0.1% to about 5% (w/v) of a suspending agent; (e)optionally up to about 2% (w/v) preservatives; and (f) water q.s. ad100%. Typically, the PP1M composition has a pH of from about 6.0 toabout 8.0, preferably a pH of from about 6.5 to about 7.5.

A composition PP1M will preferably comprise, or consistent essentiallyof, by weight based on the total volume of the composition: (a) fromabout 2% to 40% (w/v) of the paliperidone palmitate; (b) from about0.25% to 3% (w/v) of a wetting agent; (c) one or more buffering agents;(d) from about 0.25% to about 3% (w/v) of a suspending agent; (e)optionally up to about 2% (w/v) preservatives; and (f) water q.s. ad100%.

A composition for PP1M will more preferably comprise, or consistessentially of, by weight based on the total volume of the composition:(a) from about 3% to 20% (w/v) of the paliperidone palmitate; (b) fromabout 0.5% to 2% (w/v) of a wetting agent; (c) one or more bufferingagents; (d) from about 0.5% to about 2% (w/v) of a suspending agent; (e)optionally up to about 2% (w/v) preservatives; and (f) water q.s. ad100%.

In particular for PP1M, the composition comprises, or consistsessentially of, (a) from about 50 to about 250 mg/mL of paliperidonepalmitate; (b) from about 2 to about 25 mg/mL of wetting agent; (c) fromabout 2.5 to about 50 mg/mL of one or more buffering agents; (d) fromabout 5 to about 75 mg/mL of a suspending agent; (e) optionally up toabout 2% (w/v) preservatives; and (f) water q.s. ad 100%.

In other embodiments, for PP1M, the composition comprises, or consistsessentially of, (a) from about 100 to about 200 mg/mL of paliperidonepalmitate; (b) from about 5 to about 20 mg/mL of wetting agent; (c) fromabout 5 to about 25 mg/mL of one or more buffering agents; (d) fromabout 10 to about 50 mg/mL of a suspending agent; (e) up to about 2%(w/v) preservatives; and (f) water q.s. ad 100%.

In other embodiments, for PP1M, the composition comprises, or consistsessentially of, (a) from about 140 to about 180 mg/mL of paliperidonepalmitate; (b) from about 8 to about 16 mg/mL of wetting agent; (c) fromabout 5 to about 15 mg/mL of one or more buffering agents; (d) fromabout 20 to about 40 mg/mL of a suspending agent; (e) optionally up toabout 2% (w/v) preservatives; and (f) water q.s. ad 100%.

Most preferably, the active ingredient in PP1M is paliperidone palmitate(about 156 mg/mL). Most preferably, the inactive ingredients in PP1M ispolysorbate 20 (about 12 mg/mL), polyethylene glycol 4000 (about 30mg/mL), citric acid monohydrate (about 5 mg/mL), sodium dihydrogenphosphate monohydrate (about 2.5 mg/mL), disodium hydrogen phosphateanhydrous (about 5 mg/mL), sodium hydroxide (about 2.84 mg/mL) and waterfor injection. An exemplified PP1M is disclosed in Example 1.

Preferably an aqueous suspension will be made under sterile conditionsand no preservatives will be used. Appropriate methods to asepticallyprepare paliperidone palmitate are described in WO 2006/114384 which ishereby incorporated by reference herein.

The preferred aqueous dosage form contains inactive ingredients that arepolysorbate 20, polyethylene glycol 4000, citric acid monohydrate,disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphatemonohydrate, sodium hydroxide, and water for injection.

A dose or dosing is typically expressed as milligrams (mg) ofpaliperidone palmitate.

Regarding six month interval dosing, paliperidone palmitate dosing mayalso be expressed as mg equivalents (mg eq.) of paliperidone with about1092 and 1560 mg of paliperidone palmitate being equivalent to about 700and 1000 mg eq., of paliperidone, respectively. For six-month dosing itis preferred to dose patients with about 700 mg eq. to about 1000 mg eq.paliperidone or about 1092 mg to about 1560 mg paliperidone palmitate.

Regarding three month interval dosing, paliperidone palmitate dosing mayalso be expressed as mg equivalents (mg eq.) of paliperidone with about273, 410, 546, and 819 mg of paliperidone palmitate being equivalent toabout 175, 263, 350, and 525 mg eq., of paliperidone, respectively. Forthree-month dosing it is preferred to dose patients with about 175 mgeq. to about 525 mg eq. paliperidone or about 273 mg to about 819 mgpaliperidone palmitate.

Regarding one month interval dosing, paliperidone palmitate dosing mayalso be expressed as mg equivalents (mg eq.) of paliperidone with about39, 78, 117, 156, and 234 mg of paliperidone palmitate being equivalentto about 25, 50, 75, 100 and 150 mg eq., of paliperidone, respectively.For one month dosing it is preferred to dose patients with about 25 mgeq. to about 150 mg eq. paliperidone or about 39 mg to about 234 mgpaliperidone palmitate; or about 100 mg eq. to about 150 mg eq.paliperidone or about 156 mg to about 234 mg paliperidone palmitate,such as about 156 mg paliperidone palmitate or about 234 mg paliperidonepalmitate.

The term “antipsychotics” or “antipsychotic drug medication” as usedherein means any medication used to decrease or ameliorate the symptomsof psychosis in a person with a psychotic disorder.

The term “psychiatric patient” as used herein, refers to a human, whohas been the object of treatment, or experiment for a “mental disorder”and “mental illness” refer to those provided in the Diagnostic andStatistical Manual Fifth Edition (DSM 5), American PsychiatricAssociation (APA). Those of ordinary skill in the art will appreciatethat paliperidone esters (e.g. paliperidone palmitate) can beadministered to psychiatric patients for all the known uses ofrisperidone. These mental disorders include, but are not limited to,schizophrenia; bipolar disorder or other disease states in whichpsychosis, aggressive behavior, anxiety or depression is evidenced. Asset forth in DSM-5, schizophrenia refers to conditions characterized asschizophrenia, schizoaffective disorder and schizophreniform disorders.Bipolar Disorder refers to a condition characterized as a BipolarDisorder, including Bipolar I and Bipolar Disorder II. The DSM wasprepared by the Task Force on Nomenclature and Statistics of theAmerican Psychiatric Association, and provides clear descriptions ofdiagnostic categories. Pathologic psychological conditions, which arepsychoses or may be associated with psychotic features, include, but arenot limited to the following disorders that have been characterized inthe DSM. Diagnostic and Statistical Manual of Mental Disorders, Revised,5th Ed. (2013). The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forpathologic psychological conditions and that these systems evolve withmedical scientific progress. Examples of pathologic psychologicalconditions which may be treated include, but are not limited to, MildIntellectual Disability, Moderate Intellectual Disability, SevereIntellectual Disability, Profound Intellectual Disability, IntellectualDisability Severity Unspecified, Autistic Disorders, Rett's Disorder,Childhood Disintegrative Disorders, Asperger's Disorder, PervasiveDevelopmental Disorder Not Otherwise Specified,Attention-Deficit/Hyperactivity Disorder Combined Type,Attention-Deficit/Hyperactivity Disorder Predominately Inattentive Type,Attention-Deficit/Hyperactivity Disorder PredominatelyHyperactive-Impulsive Type, Attention-Deficit/Hyperactivity DisorderNOS, Conduct Disorder (Childhood-Onset and Adolescent Type, OppositionalDefiant Disorder, Disruptive Behavior Disorder Not Otherwise Specified,Solitary Aggressive Type, Conduct Disorder, Undifferentiated Type,Tourette's Disorder, Chronic Motor Or Vocal Tic Disorder, Transient TicDisorder, Tic Disorder NOS, Alcohol Intoxication Delirium, AlcoholWithdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Psychotic Disorder with Delusions, Alcohol-InducedPsychotic Disorder with Hallucinations, Amphetamine or Similarly ActingSympathomimetic Intoxication, Amphetamine or Similarly ActingSympathomimetic Delirium, Amphetamine or Similarly ActingSympathomimetic Induced Psychotic with Delusions, Amphetamine orSimilarly Acting Sympathomimetic Induced Psychotic with Hallucinations,Cannabis-Induced Psychotic Disorder with Delusions, Cannabis-InducedPsychotic Disorder with Hallucinations, Cocaine Intoxication, CocaineIntoxication Delirium, Cocaine-Induced Psychotic Disorder withDelusions, Cocaine-Induced Psychotic Disorder with Hallucinations,Hallucinogen Intoxication, Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic disorder with Delusions,Hallucinogen-Induced Psychotic disorder with Delusions,Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced AnxietyDisorder, Hallucinogen-Related Disorder Not Otherwise Specified,Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder with Delusions,Inhalant-Induced Psychotic with Hallucinations, Inhalant-Induced MoodDisorder, Inhalant-Induced Anxiety Disorder, Inhalant-Related DisorderNot Otherwise Specified, Opioid Intoxication Delirium, Opioid-InducedPsychotic Disorder with Delusions, Opioid Intoxication Delirium,Opioid-Induced Psychotic Disorder with Hallucinations, Opioid-InducedMood Disorder, Phencyclidine (PCP) or Similarly ActingArylcyclohexylamine Intoxication, Phencyclidine (PCP) or SimilarlyActing Arylcyclohexylamine Intoxication Delirium, Phencyclidine (PCP) orSimilarly Acting Arylcyclohexylamine Induced Psychotic Disorder withDelusions, Phencyclidine (PCP) or Similarly Acting ArylcyclohexylamineInduced Psychotic Disorder with Hallucinations, Phencyclidine (PCP) orSimilarly Acting Arylcyclohexylamine Mood Disorder, Phencyclidine (PCP)or Similarly Acting Arylcyclohexylamine Induced Anxiety Disorder,Phencyclidine (PCP) or Similarly Acting Arylcyclohexylamine RelatedDisorder Not Otherwise Specified, Sedative, Hypnotic or AnxiolyticIntoxication, Sedation, Hypnotic or Anxiolytic Intoxication Delirium,Sedation, Hypnotic or Anxiolytic Withdrawal Delirium, Sedation, Hypnoticor Anxiolytic Induced Persisting Dementia, Sedation, Hypnotic orAnxiolytic-Induced Psychotic Disorder with Delusions, Sedation, Hypnoticor Anxiolytic-Induced Psychotic Disorder with Hallucinations, Sedation,Hypnotic or Anxiolytic-Induced Mood Disorder, Sedation, Hypnotic orAnxiolytic-Induced Anxiety Disorder, Other (or Unknown) SubstanceIntoxication, Other (or Unknown) Substance-Induced Delirium, Other (orUnknown) Substance-Induced Persisting Dementia, Other (or Unknown)Substance-Induced Psychotic Disorder with Delusions, Other (or Unknown)Substance-Induced Psychotic Disorder with Hallucinations, Other (orUnknown) Substance-Induced Mood Disorder, Other (or Unknown)Substance-Induced Anxiety Disorder, Other (or Unknown) SubstanceDisorder Not Otherwise Specified, Obsessive Compulsive Disorder,Post-traumatic Stress Disorder, Generalized Anxiety Disorder, AnxietyDisorder Not Otherwise Specified, Body Dysmorphic Disorder,Hypochondriasis (or Hypochondriacal Neurosis), Somatization Disorder,Undifferentiated Somatoform Disorder, Somatoform Disorder Not OtherwiseSpecified, Intermittent Explosive Disorder, Kleptomania, PathologicalGambling, Pyromania, Trichotillomania, and Impulse Control Disorder NOS,Schizophreniform Disorder, Schizoaffective Disorder, DelusionalDisorder, Brief Psychotic Disorder, Shared Psychotic Disorder, PsychoticDisorder Due to a General Medical Condition with Delusions, PsychoticDisorder Due to a General Medical Condition with Hallucinations,Psychotic Disorders Not Otherwise Specified, Major Depression, SingleEpisode, Severe, without Psychotic Features, Major Depression,Recurrent, Severe, without Psychotic Features, Bipolar Disorder, Mixed,Severe, without Psychotic Features, Bipolar Disorder, Mixed, Severe,with Psychotic Features, Bipolar Disorder, Manic, Severe, withoutPsychotic Features, Bipolar Disorder, Manic, Severe, with PsychoticFeatures, Bipolar Disorder, Depressed, Severe, without PsychoticFeatures, Bipolar Disorder, Depressed, Severe, with Psychotic Features,Bipolar II Disorder, Bipolar Disorder Not Otherwise Specified,Personality Disorders, Paranoid, Personality Disorders, Schizoid,Personality Disorders, Schizotypal, Personality Disorders, Antisocial,and Personality Disorders, Borderline.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in human that is being sought by aresearcher, medical doctor or other clinician, which includesalleviation of the symptoms of the disease or disorder being treated.

Those of skill in the treatment of diseases could determine theeffective amount of paliperidone to administer for the treatment of thediseases listed above. By way of example, an effective amount ofpaliperidone for the treatment of mental disorders would be from about0.01 mg/kg to about 2 mg/kg body weight per day. For semi-annual dosingit is preferred to dose patients with about 700 mg-eq. to about 1000 mgeq. paliperidone or about 1092 mg to about 1560 mg paliperidonepalmitate. The amount of paliperidone palmitate is provided insufficient amount to provide the equivalent dose of paliperidone afterthe palmitic acid moiety is removed from the ester (e.g. 1560 mgcorresponds to paliperidone 1000 mg). For six-month dosing it ispreferred to dose patients with about 700 mg eq. to about 1000 mg eq.paliperidone or about 1092 mg to about 1560 mg paliperidone palmitate.

The following Examples are provided to illustrate some of the conceptsdescribed within this disclosure. While the Examples are considered todescribe certain embodiments, they should not be considered to limit themore general embodiments described herein. The following non-limitingexamples are provided to further support the present disclosure. Unlessotherwise noted, references to PP1M, PP3M and PP6M in Examples 4-9 referto the formulations described in Example 1 (PP1M), Example 2 (PP3M) andExample 3 (PP6M).

Example 1: One-Month Extended Release Formulation (PP1M)

Table 2 below includes an exemplary one-month extended releaseformulation (PP1M) of 100 mg/mL eq. paliperidone suitable forintramuscular (IM) injection.

TABLE 2 PP1M Concentration Component (mg/mL) Paliperidone Palmitate 156Polysorbate 20 12 Polyethylene Glycol 4000¹ 30 Citric Acid Monohydrate 5Disodium Hydrogen 5 Phosphate, Anhydrous Sodium Dihydrogen 2.5 PhosphateMonohydrate Sodium Hydroxide 2.84 Water for Injection q.s. ad 1000 μL¹equivalent to PEG 400 or MacroGol 4000

The PP1M can be provided in a prefilled syringe, with dosage strengthsranging from 25 mg eq. to 150 mg eq. obtained by filling the syringeswith different volumes of a 100 mg/mL eq. bulk suspension. Table 3 showsthe different dosage strengths, including syringe size and nominal fillvolume.

TABLE 3 PP1M Dosage Strengths with Syringe Size and Fill Volume StrengthSyringe Nominal Fill (mg) Size Volume (mL) eq. 25 0.5 mL 0.250 eq. 500.5 mL 0.500 eq. 75 1 mL Long 0.750 eq. 100 1 mL Long 1.000 eq. 125 2.25mL 1.250 eq. 150 2.25 mL 1.500

Table 4 describes the syringe components used to package the PP1M.

TABLE 4 Syringe Components for PP1M Component Description SyringeTransparent Cyclic Olefin Copolymer (COC) with Integrated Barrel LuerLock Sizes of 0.5 mL, 1 mL Long or 2.25 mL Tip Cap Bromobutyl Rubber,Dark Grey Plunger FluroTec © Coated Bromobutyl Rubber, Dark Grey (1 mLStopper Long used for 0.5 mL syringe and 1 mL Long syringe; 1-3 mL usedfor 2.25 mL syringe)

Example 2: Three Month Extended Release Formulation (PP3M)

Table 5 below includes an exemplary three-month extended releaseformulation (PP3M) of 200 mg/mL eq. paliperidone suitable forintramuscular (IM) injection.

TABLE 5 PP3M Concentration Component (mg/mL) Paliperidone Palmitate 312Polysorbate 20 10 Polyethylene Glycol 4000 75 Citric Acid Monohydrate7.5 Sodium Dihydrogen 6 Phosphate Monohydrate Sodium Hydroxide 5.4 Waterfor Injection q.s. ad 1 mL

The PP3M can be provided in a prefilled syringe, with dosage strengthsranging from 175 mg eq. to 525 mg eq. obtained by filling the syringeswith different volumes of a 200 mg/mL eq. bulk suspension. Table 6 showsthe different dosage strengths, including syringe size and nominal fillvolume.

TABLE 6 PP3M Dosage Strengths with Syringe Size and Fill Volume DoseDose as Equivalent Paliperidone as Palmitate Paliperidone SyringeNominal Fill (mg) (mg) Size Volume (mL) 273 175 1 mL Long 0.875 410 2632.25 mL 1.315 546 350 2.25 mL 1.750 819 525 2.8 mL 2.625

Table 7 describes the syringe components used to package the PP3M.

TABLE 7 Syringe Components for PP3M Component Description Syringe BarrelTransparent Cyclic Olefin Copolymer (COC) with Integrated Luer LockSizes of 1 mL Long, 2.25 mL or 2.8 mL Tip Cap Bromobutyl Rubber, DarkGrey Plunger Stopper FluroTec © Coated Bromobutyl Rubber, Dark Grey (1mL Long used for 1 mL Long syringe; and 1-3 mL used for 2.25 mL syringeand 2.8 mL syringe)

Example 3: Six Month Extended Release Formulation (PP6M)

Table 8 below includes an exemplary six-month extended releaseformulation (PP6M) of 200 mg/mL eq. paliperidone palmitate suitable forintramuscular (IM) injection.

TABLE 8 PP6M Unit Dose Unit Dose (mg/syringe (mg/syringe Concentrationin 3.5 mL in 5.0 mL Component (mg/mL) Dose) Dose) Paliperidone 312 10921560 Palmitate Polysorbate 10 35 50 20 Polyethylene 75 262.5 375 Glycol4000 Citric Acid 7.5 26.25 37.5 Monohydrate Sodium 6 21 30 DihydrogenPhosphate Monohydrate Sodium 5.4 18.9 27 Hydroxide Water for q.s. adq.s. ad q.s. ad Injection 1.0 mL 3.5 mL 5.0 mL

The PP6M can be provided in a prefilled syringe, with dosage strengthsranging from 700 mg eq. to 1000 mg eq. obtained by filling the syringeswith different volumes of a 200 mg/mL eq. bulk suspension. Table 9 showsthe different dosage strengths, including syringe size and nominal fillvolume.

TABLE 9 PP6M Dosage Strengths with Syringe Size and Fill Volume DoseDose as Equivalent Nominal Paliperidone as Fill Palmitate PaliperidoneSyringe Volume (mg) (mg) Size (mL) 1092  700 5 mL 3.5 1560 1000 5 mL 5.0

Table 10 describes the syringe components used to package the six-monthextended release formulation.

TABLE 10 Syringe Components for PP6M Component Description SyringeBarrel Transparent Cyclic Olefin Copolymer (COC) with Integrated LuerLock Tip Cap Bromobutyl Rubber Plunger Stopper Bromobutyl Rubber PlungerRod Polypropylene Backstop (aka Homopolypropylene Finger Flange)

Example 4: A Double-Blind, Randomized, Active-Controlled, Parallel-GroupStudy of Paliperidone Palmitate 6-Month Formulation Study Design

A randomized, double-blind, active-controlled, multicenter,interventional, parallel-group non-inferiority study. A flow chart ofthe study design is shown in FIG. 1 . All eligible subjects whoprogressed without relapse participated in a Screening Phase (of up to28 days), a Maintenance Phase that included 1 injection cycle witheither PP1M or PP3M (yielding a phase duration of 1 or 3 months,accordingly), and a Double-blind Phase (of 12 months). The Double-blindPhase was designed to include 4 injection cycles of PP3M (activecontrol), or 2 injection cycles of PP6M (investigational drug withalternating placebo).

Before the Maintenance Phase, some subjects participated in a TransitionPhase, with 1 to 5 injections of PP1M, if they entered the study on anoral antipsychotic, on injectable risperidone, or on PP1M previouslyinitiated but not yet stabilized. The combined Transition andMaintenance phases is referred to hereafter as the Open-Label Phase.

Randomization: 702 subjects were randomized in a 1:2 ratio to PP3M(n=224) or PP6M (n=478) treatment groups. The randomization wasstratified by study center and by the maintenance dose level (moderateor high). Consistent with global prescribing patterns, 52% werestabilized on the higher dose and 48% on the moderate dose prior torandomization.

Primary analysis population for efficacy: Double-blind Intent-to-Treat(DB ITT) analysis set, defined as all randomized subjects who receivedat least 1 dose of double-blind study medication.

Primary efficacy variable: the percentage of subjects who have notrelapsed at the end of the 12-month Double-blind Phase based on theKaplan-Meier cumulative estimate of survival.

Additional Analysis Population for efficacy: Per-protocol analysis set,defined as all randomized subjects who received at least 1 dose ofdouble-blind study medication and did not have major protocolviolations, that is, major protocol deviations that may impact efficacysuch as violations of intended study population, errors in treatmentassignment or use of excluded medication.

Analysis Population for Safety: Same as DB ITT.

Planned sample size: The sample size for the Double-blind Phase of thestudy was 549 randomized subjects, based on determinations to provide aminimum of 80% power for the primary endpoint. The sample sizedetermination includes the assumptions that the expected survival rate(percentage of subjects remaining relapse-free at 12 months) in the PP3Mgroup is 85%, and that the 1-sided significance level should be 2.5%.Given these assumptions, 549 subjects randomized in a 1:2 ratio(PP3M:PP6M) were required to demonstrate with 80% power that PP6M was noworse than PP3M by a noninferiority margin of 10% for the percentage ofsubjects remaining relapse-free at 12 months.

Primary Objective

The primary efficacy objective is to demonstrate that injection cyclesconsisting of a single administration of PP6M (700 or 1000 mg eq.) arenot less effective than 2 sequentially administered injections of PP3M(350 or 525 mg eq.) for the prevention of relapse in subjects withschizophrenia previously stabilized on corresponding doses of PP1M (100or 150 mg eq.) or PP3M (350 or 525 mg eq.).

Subject and Treatment Information

The study enrolled 841 subjects across 20 countries and 126 sites. Ofthose, 702 subjects were randomized to 1 of 2 treatment groups in a 1:2ratio (224 in PP3M and 478 in PP6M). Among the 702 subjects in the DBITT population, 23 subjects were excluded from the per-protocolpopulation, the number of subjects included in the per-protocol analysisset is 217 and 462, for the PP3M and PP6M treatment groups,respectively. In the DB ITT analysis set, 521 (74.2%) of the subjectswere white and 480 (68.4%) were male. The mean (SD) age was 40.8 (11.53)years, ranging from 18 to 69 years.

Of the 702 randomized subjects, 571 (81.3%) subjects completed the12-month Double-blind Phase without a relapse event, and 47 (6.7%)subjects completed the Double-blind Phase by having a relapse event. Themost frequent reason for withdrawal was ‘Withdrawal by subject’ by 54(7.7%) subjects.

Efficacy

The primary efficacy endpoint was the percentage of subjects who havenot relapsed by the end of the 12-month Double-blind Phase based on theKaplan-Meier 12-Month cumulative estimate of survival. Statisticalanalysis tests were conducted at the two-sided 0.05 significance level.

Primary Efficacy Endpoint

In the DB ITT population, 11 (4.9%) subjects in the PP3M group and 36(7.5%) subjects in the PP6M group experienced a relapse event during the12 Month Double-blind Phase. The estimated difference (95% CI) betweenthe treatment groups (PP6M-PP3M) in percentages of subjects who remainedrelapse free is −2.9% (−6.8%, 1.1%). The lower bound of the 95%confidence interval is larger than the pre-specified non-inferioritymargin of −10%, therefore, PP6M can be declared to be non-inferior toPP3M (FIG. 2 ).

In the per-protocol analysis population, 10 (4.6%) subjects in the PP3Mgroup and 35 (7.6%) subjects in the PP6M group experienced a relapseevent during the Double-blind Phase. The results are similar to thatobtained for the DB ITT analysis population, further confirming thenon-inferiority of PP6M to PP3M (FIG. 3 ).

Supplementary analyses were conducted for the primary efficacy analysisby including data collected during the follow-up phase for subjects whowithdrew from the Double-blind phase. Results are consistent withprimary efficacy analysis.

For the DB ITT analysis population, the ratio (95% CI) of theinstantaneous risk (hazard) of relapse for a subject in the PP6Mtreatment group during the Double-blind Phase versus the risk for asubject in the PP3M in the Double-blind Phase was 1.57 (95% CI: 0.8,3.08), based upon a Cox Proportional Hazards Model with treatment as theonly factor. Accordingly, the hazard rate in the PP6M subjects is 1.57times the hazard rate of PP3M treated subjects.

Safety

Overall, 297/478 (62.1%) subjects in the PP6M group and 131/224 (58.5%)subjects in the PP3M group experienced at least one TEAE during theDouble-blind Phase. The most common (>5%) TEAEs during the Double-blindPhase were weight increased (8.4%), injection site pain (7.7%), headache(6.7%), upper respiratory tract infection (5.0%) for the PP6M group, andweight increased (7.6%), nasopharyngitis (5.8%), headache (5.4%) for thePP3M group.

There were 1 and 3 deaths in the Open-Label (combined Transition andMaintenance phases) and Double-blind Phases, respectively. Among the 3deaths in the Double-blind Phase, 1 (0.2%) was for the PP6M group, and 2(0.9%) were for the PP3M group.

Thirty-nine subjects (24 [5.0%] in PP6M, 15 [6.7%] in PP3M) experiencedserious TEAEs during the Double-blind Phase.

During the Double-blind Phase, study medication was permanently stoppeddue to an adverse event with the following incidence across treatmentgroups: 16 (3.3%) subjects in the PP6M group, and 6 (2.7%) subjects inthe PP3M group.

Abbreviations

DB: double-blind.

OL: open-label.

MA: maintenance.

PANSS: positive and negative syndrome scale for schizophrenia.

PP: per-protocol.

KM: Kaplan-Meier.

ITT: intent to treat.

SD: standard deviation.

CI: confidence interval.

TEAE: treatment-emergent adverse event.

Example 5: Dosing Conversion

Conversion from PP1M or PP3M to PP6M doses are described in Table 11below.

TABLE 11 Paliperidone palmitate Dosing Conversion Tables PP6M Doses forAdult Patients Adequately Treated with PP1M If the Last Dose of PP1M is:Transition to PP6M dose of: 156 mg (100 mg eq.) 1092 mg (700 mg eq.) 234mg (150 mg eq.) 1560 mg (1000 mg eq.) PP6M Doses for Adult PatientsAdequately Treated with PP3M If the Last Dose of PP3M is: Transition toPP6Mdose of: 546 mg (350 mg eq.) 1092 mg (700 mg eq.) 819 mg (525 mgeq.) 1560 mg (1000 mg eq.)

Patients who are adequately treated with either PP1M (after at least 4months of treatment) or PP3M (at least one 3-month injection cycle) anddo not require dose adjustment may be switched to PP6M. PP6M should beinitiated in place of the next scheduled dose of PP1M (±7 days) or PP3M(±14 days). The dose of PP6M should be based on the previouscorresponding dose of PP3M or PP1M, as shown in Table 11, supra. Whentransitioning to PP6M from PP1M, to establish a consistent maintenancedose, it is recommended that the last two doses of PP1M be the samedosage strength before starting PP6M.

A prior treatment period with PP1M or PP3M ensures that paliperidoneplasma concentrations are at or approach steady state prior to thetransition to PP6M.

Model-based simulations suggest that subjects transitioning directlyfrom PP1M (after at least 4-months of treatment) to PP6M have similarpaliperidone exposure levels when compared to those subjects whotransition from PP3M (after at least one 3-month injection cycle) toPP6M. Consequently, subjects may be transitioned directly from PP1M toPP6M, without transitioning to PP3M first prior to starting PP6M dosing.

Example 6—Pharmacokinetic Profile of PP6M in Subjects Transitioning fromPP1M or PP3M Objective

The objective of this trial was to assess the pharmacokinetic (PK)profile of PP6M (700 or 1000 mg eq.) administered in the gluteal musclein subjects with schizophrenia who have transitioned from correspondingdoses of PP1M (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).

Subjects and Methods

This clinical trial was a randomized, double-blind, active-controlled,multicenter, interventional, parallel-group study. All eligible subjectswho progressed without relapse participated in a Screening Phase (of upto 28 days), a Maintenance Phase that included 1 injection cycle witheither paliperidone palmitate 1-month (PP1M) or paliperidone palmitate3-month (PP3M) (yielding a phase duration of 1 or 3 months,accordingly), and a double-blind Phase (of 12 months). The double-blindPhase was designed to include 2 injection cycles of paliperidonepalmitate 6 month (PP6M) (investigational drug with alternating placebo)or 4 injection cycles of PP3M (active control). Multiple pharmacokineticblood samples were collected during the open label phase (PP1M and PP3M)as well as double-blind phase (PP3M and PP6M) of the trial to determinethe time course of paliperidone plasma concentrations. The aim of the PKevaluations was to characterize the time course of plasma paliperidoneconcentrations and PK parameters such as maximum and minimum plasmaconcentrations and their associated timing. Therefore, 3 PK samples werescheduled weekly around the expected paliperidone peak at approximately1 month after the PP6M dose, and 6 PK samples were scheduled weekly whenapproaching the end of the 6-month dosing interval.

Results

Pharmacokinetics of Paliperidone in the Maintenance Phase after PP1M andPP3M Dosing

After administration of PP1M in the Maintenance Phase, median t_(max)after a 100 mg eq. dose was 8 days and was comparable to median t_(max)of 7 days after a 150 mg eq. dose. After administration of 350 or 525 mgeq. (PP3M) median t_(max) was comparable and was 28 days. Based onvisual inspection, C_(trough), C_(max), and AUC_(3M) seemed to increasedose proportionally for both PP1M and PP3M. Dose-normalized meanC_(trough), C_(max), and AUC_(3M) were comparable for PP1M and PP3M. ThePeak/Trough Ratio was also comparable for PP1M and PP3M.

Pharmacokinetics of Paliperidone in the Double-Blind Phase after PP6Mand PP3M Dosing.

Mean dose-normalized trough concentrations were comparable for PP3M andPP6M at Day 1 (24.6 ng/mL and 25.0 ng/mL, respectively); at latertimepoints the subjects who received PP6M had approximately 25-28% lowertrough concentrations (16.7 ng/mL at Day 183 and 17.3 ng/mL at Day 365)compared to subjects who received PP3M (22.2 ng/mL at Day 183 and 24.1ng/mL at Day 365). After the first administration of 350 or 525 mg eq.PP3M or 700 or 1000 mg eq. PP6M in the Double-blind Phase, mediant_(max) was comparable for all treatments, i.e., approximately 28 days.Similarly, after administration of 350 or 525 mg eq. PP3M or 700 or 1000mg eq. PP6M in the second 6 months of the Double-blind Phase, mediant_(max) was comparable and ranged between 29 and 32 days. Based onvisual inspection, C_(trough), C_(max), and AUC_(6M) seemed to increasedose proportionally for PP6M (700 or 1000 mg eq.) after administrationof each, the first and second dose, in the double-blind phase.Similarly, PK exposure parameters for paliperidone (C_(trough), C_(max),and AUC_(6M)) seem to be dose proportional, after the first and thirddoses of PP3M doses (350 or 525 mg eq.) in the Double-blind Phase.Dose-normalized mean C_(max) was slightly higher (1.4 to 1.5-fold) forPP6M, when compared to PP3M. Mean dose normalized total paliperidoneexposure (AUC_(6M)) was comparable in the Double-blind Phase after PP3Mand PP6M dosing. The results are summarized below in Table 12, as wellas in FIG. 4 .

Median peak-to-trough ratios after PP3M administration in theMaintenance and Double-blind Phase were comparable across doses, rangingfrom 1.85 to 1.92 and 1.66 to 2.11 in the Maintenance- and Double-blindPhases, respectively. Median peak-to-trough ratios in the double blindphase after PP6M administrated once every six months ranged from2.71-3.41. Median peak to trough ratios after PP6M administration in theDouble-blind Phase were comparable across doses and were slightly higherafter the first administration (ranging from 3.32 to 3.41) compared tothe second administration (ranging from 2.71 to 3.20).

After stratification per administered dosage, maintenance phase product,injection site in maintenance phase, gender, age, and creatinineclearance category for several groups, no clinically meaningfuldifference was observed as the ranges were overlapping due to the highinter-subject variation for the PP3M and PP6M subgroups for C_(max),AUC_(6M).

Dose normalized mean paliperidone exposure (C_(max), AUC_(6M)) afterPP6M administration in the Double-blind Phase was comparable betweensub-groups of subjects who receive PP1M or PP3M in the maintenancephase.

TABLE 12 PK Data for Patients Given PP3M and PP6M Paliperidone PK (mean[SD], t_(max): median PP3M PP3M PP6M PP6M [range]) (350 mg eq.) (525 mgeq.) (700 mg eq.) (1000 mg eq.) DB 0-6 Months n 98^(a) 112^(b) 222^(c)229^(d) t_(max) (h) 670.80 (0.00-2256.57) 679.92 (0.00-2325.15) 671.09(0.00-4367.42) 674.00 (0.00-4366.57) t_(max) (days) 27.95 (0.00-94.02)28.33 (0.00-96.88) 27.96 (0.00-181.98) 28.08 (0.00-181.94) C_(trough)(ng/mL) 19.8 (9.82) 34.1 (19.7) 17.2 (11.5) 23.2 (16.2) C_(max) (ng/mL)42.5 (23.7) 67.0 (39.1) 68.8 (40.4) 93.6 (61.2) AUC_(3M) (ng · h/mL)64357 (31797) 103499 (51173) — — AUC_(6M) (ng · h/mL) 128713 (63593)206998 (102347) 152555 (73249) 204527 (97213) DB 6-12 Months n 87^(e)101^(f) 193^(g) 197^(h) t_(max) (h) 766.17 (23.67-2301.80) 692.33(44.62-2233.83) 717.87 (43.33-4367.33) 720.45 (0.00-3623.42) t_(max)(days) 31.92 (0.99-95.91) 28.85 (1.86-93.08) 29.91 (1.81-181.97) 30.02(0.00-150.98) C_(trough) (ng/mL) 22.7 (10.8) 34.8 (20.6) 17.6 (11.7)24.3 (12.8) C_(max) (ng/mL) 44.1 (21.1) 67.2 (55.1) 67.9 (69.8) 84.2(47.0) AUC_(3M) (ng · h/mL) 68410 (27774) 103004 (57770) — — AUC_(6M)(ng · h/mL) 136819 (55549) 206009 (115541) 143258 (66364) 191933 (81831)^(a)n = 92 for C_(trough) and n = 97 for AUC_(3M) and AUC_(6M) ^(b)n =108 for C_(trough) ^(c)n = 182 for C_(trough) and n = 215 for AUC_(6M)^(d)n = 181 for C_(trough) and n = 222 for AUC_(6M) ^(e)n = 82 forC_(trough) and n = 84 for AUC_(3M) and AUC_(6M) ^(f) n = 95 forC_(trough) ^(g) n = 160 for C_(trough) and n = 185 for AUC_(6M) ^(h) n =177 for C_(trough) and n = 194 for AUC_(6M)

Example 7—Dosing Window for PP6M Maintenance treatment

Population PK Simulations: Effects of Extending or Shortening the DosingInterval on the C_(max) and C_(trough)

Acceptability of a dosing window 2 weeks before and 3 weeks after theregularly scheduled 6-month maintenance injection was evaluated asfollows:

The moderate PP6M dose strength (700 mg eq.) was used to simulate theworst-case scenario where extending the dosing interval results in thelower C_(trough). As shown in Table 13, for injections delayed by 1, 2and 3 weeks relative to the scheduled 6-month injection after reachingPP6M steady state on 700 mg eq., the median C_(trough) decreased from15.8 ng/mL to 15.3 (−3.2%), 14.9 (−5.6%), and 14.4 (−8.9%) ng/mL,respectively; and

The highest PP6M dose strength (1000 mg eq.) was used to simulate theworst-case scenario where shortening the dosing interval results in thehighest C_(max). As shown in Table 13, reproduced below, for injectionsadministered 1 week earlier and 2 weeks earlier relative to thescheduled 6-month injection after reaching PP6M steady state on 1000 mgeq., the median C_(max) increased from 76.1 ng/mL to 76.3 (+0.3%) and to76.6 (+0.7%), respectively.

TABLE 13 Pharmacokinetic Data at PP6M Steady State (dosing 1-2 weeksearly and 1-3 weeks late relative to the scheduled 6-month injection)C_(max) % change C_(trough) % change Dose Regime (ng/mL)^(a) vs base(ng/mL)^(b) vs base High Dose base PP6M 76.1 — 1 week earlier 76.3 +0.3%2 weeks earlier 76.6 +0.7% Moderate Dose base PP6M 15.8 — 1 week later15.3 −3.2% 2 weeks later 14.9 −5.7% 3 weeks later 14.4 −8.9%

Duration of Clinical Effect Based on Median Time to Relapse in RelapsePrevention Studies

PK simulations were conducted to evaluate the relationship betweenmedian time to relapse and the time point at which the medianpaliperidone concentration decreased to 7.5 ng/mL, followingadministration of the last steady-state dose in each study prior to theDouble-blind phase (oral paliperidone ER 12 mg, PP1M 150 mg eq, PP3M 525mg eq, and PP6M 1000 mg eq.), as shown in FIG. 5 . An apparent delaylasting from several weeks to several months was observed between thetime point when the median plasma paliperidone concentration decreasedto 7.5 ng/mL and the median time to relapse, i.e., the time point whenhalf of the subjects had experienced relapse, while the other half ofthe subjects either relapsed later or did not relapse during the study.Thus, it appears that the therapeutic effect is more prolonged than theexpected effect based on the 7.5 ng/mL threshold, and the relapseprotection window extends farther in the positive direction.

Regarding FIG. 5 , the simulations depict the decay in paliperidoneplasma concentrations after stopping steady-state dose administrationsof: 1) Oral paliperidone ER, 12 mg; 2) PP1M 150 mg eq.; 3) PP3M 525 mgeq.; and 4) PP6M 1000 mg eq.; using the high dose level for eachformulation as a representative scenario. Median time to relapse wascalculated from the placebo group from the following studies: oralpaliperidone ER (R076477SCH301), PP1M (R092670PSY3001), and PP3M(R092670PSY3012) based on the final Kaplan-Meier estimates.

Therefore, a dosing window of up to 2 weeks earlier and up to 3 weekslater than the target 6-month date for maintenance treatment with PP6Mis possible and provides scheduling flexibility and enhances treatmentadherence, without loss of efficacy or worsening of side effects.

Example 8: Missed Dosing

Based on population pharmacokinetic simulations, the followingguidelines are provided in the event of missed doses of PP6M beyond thedosing-window: If more than 6 months and 3 weeks up to but less than 8months have elapsed since the last injection of PP6M, the followingre-initiation regimen may be used.

TABLE 14 Re-initiation Regimen After Missing over 6 Months and 3 Weeksup to but less than 8 Months of PP6M Administer Then administer PP1Minto PP6M into gluteal If the Last Dose: deltoid muscle muscle 1 monthlater of PP6M was Day 1 1 month after Day 1 1092 mg (700 mg eq.) 156 mg(100 mg eq.) 1092 mg (700 mg eq.) 1560 mg (1000 mg eq.) 234 mg (150 mgeq.) 1560 mg (1000 mg eq.)

If 8 months up to and including 11 months have elapsed since the lastinjection of PP6M, the following re-initiation regimen may be used.

TABLE 15 Re-initiation Regimen After Missing over 8 Months up to 11Months of PP6M Administer Then administer PP1M into PP6M into If thelast dose of deltoid muscle gluteal muscle PP6M was: Day 1 Day 8 1 monthafter Day 8 1092 mg 156 mg 156 mg 1092 mg (700 mg eq.) (100 mg eq.) (100mg eq.) (700 mg eq.) 1560 mg 156 mg 156 mg 1560 mg (1000 mg eq.) (100 mgeq.) (100 mg eq.) (1000 mg eq.)

If more than 11 months have elapsed since the last injection of PP6M,re-initiate treatment with PP1M as described in prescribing informationfor the PP1M product. PP6M can then be resumed after the patient hasbeen adequately treated with PP1M for at least 4 months. To establish aconsistent maintenance dose, it is recommended that the last two dosesof PP1M should be the same dose strength before re-starting PP6M.

The re-initiation regimen after missed dosing and the timing ofcontinuation of the PP6M maintenance regime depends on the time intervalsince the last PP6M dose. These recommendations are based on simulationsperformed to address the scenario of a missed dose in patients that havebeen stabilized on treatment with PP6M, as shown in FIGS. 6-8 . Criteriawere to achieve a quick return to paliperidone plasma concentrations asbefore the missed dose, without creating an overshoot due the appliedre-initiation regimen.

Regarding FIG. 6 , the middle solid line represents the medianpaliperidone concentration and the shaded area between the bottom andtop dotted lines represents the 90% prediction band. Standard PP1M4-month treatment in deltoid (initiation doses followed by maintenancedoses) followed by PP6M dosing. The delay in the last PP6M dose isindicated, and re-initiation, performed with one dose of 150 mg eq. PP1Min deltoid for the high dose level, is indicated. The light stipple arearepresents the range from trough to peak concentration (defined by the90% prediction band) before the PP6M dosing interval changed.

Regarding FIG. 7 , the middle solid line represents the medianpaliperidone concentration and the shaded area between the bottom andtop dotted lines represents the 90% prediction band. Standard PP1M4-month treatment in deltoid (initiation doses followed by maintenancedoses) followed by PP6M dosing. The delay in the last PP6M dose isindicated, and re-initiation, performed with two doses of 100 mg eq.PP1M in deltoid, is indicated. The light stipple area represents therange from trough to peak concentration (defined by the 90% predictionband) before the PP6M dosing interval changed.

Regarding FIG. 8 , the middle solid line represents the medianpaliperidone concentration and the shaded area between the bottom andtop dotted lines represents the 90% prediction band. Standard PP1M4-month treatment in deltoid (initiation doses followed by maintenancedoses) followed by PP6M dosing. The delay in the last PP6M dose isindicated, and re-initiation is performed as a 4-month PP1M treatment indeltoid. The light stipple area represents the range from trough to peakconcentration (defined by the 90% prediction band) before the PP6Mdosing interval changed.

These guidelines provide a mechanism by which patients can resumetreatment with PP6M in case they become fully or partially non-adherent,thereby reducing the need to start treatment de novo.

Example 9—Blood Lipid Stabilization Associated with PP6M Treatment

Based on the findings of the studies set forth in Example 4, patientswith schizophrenia stabilized on shorter acting paliperidoneformulations (PP1M, PP3M) who were switched to the longer actingformulation (PP6M) showed greater beneficial effect in blood lipidsduring Double blind phase (12 months) compared to patients treated withPP3M (active comparator) during the 12 month Double-blind phase.

The timing of the blood samples were at the trough (lowest PK values)for both treatments: PP3M and PP6M. Because PP3M is administered every 3months, the lowest levels are expected to be prior to the nextinjection. Similarly, for the PP6M group, the trough levels are expectedto be at month 6. It was expected that the lipid values for bothtreatment groups would be similar. But even at trough time points, thereis a numerical advantage to the PP6M treatment group for all four of thelipid parameters. Mean values for the four key lipid parameters overtime during the double-blind phase are presented below. Patients in thisstudy were instructed to have labs drawn after an overnight fast (or atleast 8 hours). For cholesterol, LDL, and triglycerides, an increase isconsidered to be a worsening. For HDL, an increase is considered to bebeneficial:

TABLE 16 PP3M PP6M VISIT n mean std N Mean std Fasting Double-BlindBaseline 193 187.2 40.7 407 184.8 40.3 Cholesterol Double-Blind Month 6183 183.7 38.0 407 184.0 37.7 (mg/dL) Double-Blind Month 12 159 192.840.3 328 187.7 39.8 Fasting HDL Double-Blind Baseline 193 47.2 14.2 40749.0 13.3 (mg/dL) Double-Blind Month 6 183 46.6 13.8 407 48.5 13.1Double-Blind Month 12 158 47.3 13.4 328 48.0 12.8 Fasting LDLDouble-Blind Baseline 193 111.8 36.5 407 109.2 34.4 (mg/dL) Double-BlindMonth 6 183 108.0 34.1 407 107.9 31.8 Double-Blind Month 12 158 115.335.8 324 111.5 34.1 Fasting Double-Blind Baseline 193 150.1 138.6 407135.4 89.4 Triglycerides Double-Blind Month 6 183 150.2 113.7 407 139.386.2 (mg/dL) Double-Blind Month 12 158 156.3 113.0 324 142.6 93.4

While showing a beneficial effect on blood lipids, the study data showednon-inferior efficacy of PP6M compared to PP3M on the primary endpointof time to relapse at the end of the 12-month period in bothintent-to-treat and per-protocol analysis sets. The safety profileobserved for PP6M was consistent with previous studies of paliperidonepalmitate 1-month (PP1M) and 3-month (PP3M) formulations with no newsafety signals emerging.

In clinical practice, it can also be important to understand if patientsshift from one category to another in terms of lipid risk. The tablebelow presents the proportion of patients who shifted from one categoryto another during the course of the double-blind period:

TABLE 17 Fasting Lipids: Treatment-Emergent Shifts from Baseline (DB)during the Double-Blind Phase PP3M PP6M (N = 224) (N = 478) FastingCholesterol (mg/dL) 194 423 <200 mg/dL to >= 240 mg/dL 2 (1.0%) 3 (0.7%)Fasting HDL Cholesterol (mg/dL) 194 423 >=40 mg/dL to < 40 mg/dL 28(14.4%) 55 (13.0%) Fasting LDL Cholesterol (mg/dL) 194 423 <100 mg/dLto >= 160 mg/dL 1 (0.5%) 2 (0.5%) Fasting Triglycerides (mg/dL) 194 423<150 mg/dL to >= 200 mg/dL 22 (11.3%) 22 (5.2%) For each fastingparameter, subjects with both Baseline(DB) record and any post baseline(DB) record during Double-Blind Phase are included in the denominator.

The data above is further broken down by BMI category (normal,overweight, or obese). The baseline BMI of each patient was calculatedbased on their weight (kg) divided by height (m²) at the double-blindbaseline timepoint. Patients with a BMI of greater than or equal to 30were considered obese, those with BMI of 25 to less than 30 wereconsidered overweight, and those with a BMI of less than 25 wereconsidered normal. In nearly every category and BMI subgroup, patientstreated with PP6M display a numerical advantage:

TABLE 18 Fasting Lipids: Treatment-Emergent Shifts from Baseline (DB)during the Double-Blind Phase by Baseline (DB) BMI Group: Normal < 25,Overweight 25 -< 30 vs. Obese >= 30 PP3M PP6M (N = 224) (N = 478) Normal< 25 Fasting Cholesterol (mg/dL) 65 123 <200 mg/dL to >= 240 mg/dL 1(1.5%) 1 (0.8%) Fasting HDL Cholesterol (mg/dL) 65 123 >=40 mg/dL to <40 mg/dL 8 (12.3%) 14(11.4%) Fasting LDL Cholesterol (mg/dL) 65 123 <100mg/dL to >= 160 mg/dL 0 0 Fasting Triglycerides (mg/dL) 65 123 <150mg/dL to >= 200 mg/dL 7 (10.8%) 7 (5.7%) Obese >= 30 Fasting Cholesterol(mg/dL) 65 137 <200 mg/dL to >= 240 mg/dL 0 1 (0.7%) Fasting HDLCholesterol (mg/dL) 65 137 >= 40 mg/dL to < 40 mg/dL 11 (16.9%) 19(13.9%) Fasting LDL Cholesterol (mg/dL) 65 137 <100 mg/dL to >= 160mg/dL 0 1 (0.7%) Fasting Triglycerides (mg/dL) 65 137 <150 mg/dL to >=200 mg/dL 6 (9.2%) 8 (5.8%) Overweight 25-< 30 Fasting Cholesterol(mg/dL) 64 163 <200 mg/dL to >= 240 mg/dL 1 (1.6%) 1 (0.6%) Fasting HDLCholesterol (mg/dL) 64 163 >=40 mg/dL to < 40 mg/dL 9(14.1%) 22 (13.5%)Fasting LDL Cholesterol (mg/dL) 64 163 <100 mg/dL to >= 160 mg/dL 1(1.6%) 1 (0.6%) Fasting Triglycerides (mg/dL) 64 163 <150 mg/dL to >=200 mg/dL 9(14.1%) 7 (4.3%) For each fasting parameter, subjects withboth Baseline(DB) record and any post baseline (DB) record duringDouble-Blind Phase are included in the denominator.

What is claimed is:
 1. A method for mitigating an adverse change inblood lipid profile of a patient in need thereof who has been treatedwith a paliperidone palmitate extended-release injectable suspension ateither one-month intervals (PP1M) or three-month intervals (PP3M),comprising transitioning the patient to a paliperidone palmitateextended-release injectable suspension having a six month dosinginterval (PP6M) by administering to the patient a last dose of the PP1Mor the PP3M and then administering an initial dose of the PP6M.
 2. Themethod of claim 1, wherein the patient has been treated with the PP1Mfor at least four months.
 3. The method of claim 1, wherein the patienthas been treated with the PP3M for at least one 3-month interval.
 4. Themethod of claim 2, wherein the initial dose of the PP6M is administeredabout 1 month (±7 days) after the last dose of the PP1M is administered.5. The method of claim 4, wherein: when the last dose of the PP1Mcomprises about 156 mg of paliperidone palmitate, the initial dose ofthe PP6M comprises about 1092 mg of paliperidone palmitate.
 6. Themethod of claim 4, wherein: when the last dose of the PP1M comprisesabout 234 mg of paliperidone palmitate, the initial dose of the PP6Mcomprises about 1560 mg of paliperidone palmitate.
 7. The method ofclaim 3, wherein the initial dose of the PP6M is administered about 3months (±14 days) after the last dose of the PP3M is administered. 8.The method of claim 7, wherein: when the last dose of the PP3M comprisesabout 546 mg of paliperidone palmitate, the initial dose of the PP6Mcomprises about 1092 mg of paliperidone palmitate.
 9. The method ofclaim 7, wherein: when the last dose of the PP3M comprises about 819 mgof paliperidone palmitate, the initial dose of the PP6M comprises about1560 mg of paliperidone palmitate.
 10. The method of claim 1, whereinthe adverse change is an adverse change in fasting low densitylipoprotein (LDL), fasting triglycerides, fasting total cholesterol, orfasting high density lipoprotein (HDL), or combinations thereof.
 11. Themethod of claim 10, wherein the patient experienced apaliperidone-induced increase of LDL, fasting triglycerides, or fastingtotal cholesterol, or a paliperidone-induced decrease of HDL, orcombinations thereof, prior to the transition to the PP6M.
 12. Themethod of claim 11, wherein the patient suffers from an additionalmetabolic symptom prior to the transition to the PP6M.
 13. The method ofclaim 12, wherein the metabolic symptom is obesity, high blood pressure,insulin resistance, or combinations thereof.
 14. The method of claim 10,wherein the patient's blood lipid profile is assessed at the time of theinitial dose of the PP6M.
 15. The method of claim 7, wherein the PP3M orPP6M comprises: about 280 mg/mL to about 350 mg/mL of the paliperidonepalmitate; about 8 mg/mL to about 12 mg/mL of a wetting agent; one ormore buffering agents; about 65 mg/mL to about 85 mg/mL of a suspendingagent; and water q.s. ad 100%.
 16. The method of claim 15, wherein thePP3M or PP6M is from about pH 6.0 to about pH 8.0.
 17. The method ofclaim 15, wherein the one or more buffering agents comprise citric acidmonohydrate, sodium dihydrogen phosphate monohydrate, disodium hydrogenphosphate anhydrous, or sodium hydroxide.
 18. The method of claim 15,wherein the PP3M or PP6M comprises: about 312 mg/mL of paliperidonepalmitate; about 10 mg/mL of polysorbate 20; and about 75 mg/mL ofpolyethylene glycol
 4000. 19. The method of claim 4, wherein the PP1Mcomprises: about 140 mg/mL to about 180 mg/ml of the paliperidonepalmitate; about 8 mg/mL to about 16 mg/ml of a wetting agent; one ormore buffering agents; about 20 mg/mL to about 40 mg/ml of a suspendingagent; and water q.s. ad 100%.
 20. The method of claim 19, wherein thePP1M is from about pH 6.0 to about pH 8.0.
 21. The method of claim 19,wherein the one or more buffering agents comprise citric acidmonohydrate, sodium dihydrogen phosphate monohydrate, disodium hydrogenphosphate anhydrous, or sodium hydroxide.
 22. The method of claim 19,wherein the PP1M comprises: about 156 mg/mL of paliperidone palmitate;about 12 mg/mL of polysorbate 20; and about 30 mg/mL of polyethyleneglycol
 4000. 23. The method of claim 19, wherein the PP6M comprises:about 280 mg/mL to about 350 mg/mL of the paliperidone palmitate; about8 mg/mL to about 12 mg/mL of a wetting agent; one or more bufferingagents; about 65 mg/mL to about 85 mg/mL of a suspending agent; andwater q.s. ad 100%.
 24. The method of claim 23, wherein the PP6M is fromabout pH 6.0 to about pH 8.0.
 25. The method of claim 23, wherein theone or more buffering agents comprise citric acid monohydrate, sodiumdihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous,or sodium hydroxide.
 26. The method of claim 23, wherein the PP6Mcomprises: about 312 mg/mL of paliperidone palmitate; about 10 mg/mL ofpolysorbate 20; and about 75 mg/mL of polyethylene glycol
 4000. 27. Themethod of claim 8, wherein the PP3M and PP6M each comprise about 280mg/mL to about 350 mg/mL of paliperidone palmitate.
 28. The method ofclaim 8, wherein the PP3M and PP6M each comprise about 312 mg/mL ofpaliperidone palmitate.
 29. The method of claim 9, wherein the PP3M andPP6M each comprise about 280 mg/mL to about 350 mg/mL of paliperidonepalmitate.
 30. The method of claim 9, wherein the PP3M and PP6M eachcomprise about 312 mg/mL of paliperidone palmitate.
 31. The method ofclaim 5, wherein the PP1M comprises about 140 mg/mL to about 180 mg/mlof paliperidone palmitate and the PP6M comprises about 280 mg/mL toabout 350 mg/mL of paliperidone palmitate.
 32. The method of claim 5,wherein the PP1M comprises about 156 mg/mL of paliperidone palmitate andthe PP6M comprises about 312 mg/mL of paliperidone palmitate.
 33. Themethod of claim 6, wherein the PP1M comprises about 140 mg/mL to about180 mg/ml of paliperidone palmitate and the PP6M comprises about 280mg/mL to about 350 mg/mL of paliperidone palmitate.
 34. The method ofclaim 6, wherein the PP1M comprises about 156 mg/mL of paliperidonepalmitate and the PP6M comprises about 312 mg/mL of paliperidonepalmitate.